Novel thienopyrimidine derivatives, processes for the preparation thereof and therapeutic uses thereof

ABSTRACT

The present invention relates to compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R6 is —CONH 2  or a —C(R α )(R β )(OH) group; R is a substituted phenyl or heteroaryl group; R7 is an optionally substituted aryl or heteroaryl group. 
     Process for the preparation thereof and therapeutic use thereof.

The present invention relates to novel thienopyrimidine derivatives, toprocesses for the preparation thereof, and also to the therapeutic usesthereof, in particular as anticancer agents via ALK kinase inhibition.

The present invention also relates to pharmaceutical compositionscontaining these derivatives, which have anticancer activity via ALKkinase modulation.

At the current time, most commercial compounds used in chemotherapy arecytotoxic compounds which pose considerable problems in terms of sideeffects and tolerance by patients. These effects could be limitedinsofar as the medicines used act selectively on cancer cells, withexclusion of healthy cells. One of the solutions for limiting theadverse effects of chemotherapy can therefore consist of the use ofmedicines which act on metabolic pathways or constituent elements ofthese pathways, expressed predominantly in cancer cells, and which wouldbe expressed little or not at all in healthy cells. Protein kinases area family of enzymes which catalyze the phosphorylation of hydroxylgroups of specific residues of proteins, such as tyrosine, serine orthreonine residues. Such phosphorylations can widely modify the functionof proteins: thus, protein kinases play an important role in theregulation of a large variety of cell processes, including in particularmetabolism, cell proliferation, cell adhesion and motility, celldifferentiation or cell survival, some protein kinases playing a centralrole in the initiation, development and completion of cell cycle events.

Among the various cell functions in which the activity of a proteinkinase is involved, certain processes represent attractive targets fortreating certain diseases. As an example, mention may particularly bemade of angiogenesis and control of the cell cycle and also the controlof cell proliferation, in which processes protein kinases can play anessential role. These processes are in particular essential for thegrowth of solid tumours and also other diseases. In particular,molecules which inhibit such kinases are capable of limiting undesiredcell proliferations such as those observed in cancers, and can intervenein the prevention, regulation or treatment of neurodegenerative diseasessuch as Alzheimer's disease or else neuronal apoptosis.

The ALK kinase (or anaplastic lymphoma kinase) is a tyrosine kinasereceptor, which belongs to the insulin receptor subfamily. ALK isexpressed predominantly in the brain of newborn babies, which suggests apossible role for ALK in brain development.

ALK was initially identified in the form of a constitutively activated,oncogenic fusion protein in large cell anaplastic lymphomas. It has inparticular been demonstrated that the mutant protein nucleophosmin(NMP)/ALK has an active tyrosine kinase domain responsible for itsoncogenic activity (Falini, B. et al., Blood, 1999, 94, 3509-3515;Morris, S. W. et al., Brit. J. Haematol, 2001, 113, 275-295; Duyster etal.; Kutok & Aster). Recently, fusion proteins of similar forms havebeen identified in other types of human cancers: DLBCL diffuse largeB-cell lymphoma, IMT inflammatory myofibroblastic tumour, ovariancancer, breast cancer, colorectal cancer, glioblastoma, and also innon-small cell lung carcinomas (NSCLC). NSCLC cancers are common andlethal in human beings. Moreover, ALK gene amplifications and alsoactive mutations have been found in neuroblastomas. In healthy adults,ALK expression is low and remains confined to neuronal tissues. ALK istherefore a therapeutic target in many types of cancers (Cheng and Ott,Anti-Cancer Agents in Medicinal Chemistry, 2010, 10, 236-249).

The objective of the present invention is to provide novel ALKkinase-inhibiting compounds intended for cancer treatment.

Thus, the present invention relates to compounds of formula (I):

-   -   wherein:    -   R6 is —CONH₂ or a —C(R_(α))(R_(β))(OH) group in which R_(α) and        R_(β) are, independently of one another, a hydrogen atom or a        (C₁-C₆) alkyl group or together form, with the carbon atom which        bears them, a 3- to 5-membered carbocycle;    -   R is a phenyl or heteroaryl group substituted with R1, R′1, R2        and R3;    -   R1 is a hydrogen atom or is selected from the following groups:        (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl and aryl, these        groups being optionally substituted with one or several        substituents selected, independently in each instance, from:        amino, hydroxyl, thiol, halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,        (C₁-C₆)alkylthio, (C₁-C₆)alkylamino, aryloxy, aryl(C₁-C₆)alkoxy,        cyano, halo(C₁-C₆)alkyl, carboxyl and carboxy(C₁-C₆)alkyl;    -   R′1 is a hydrogen atom or a (C₁-C₆)alkoxy group;    -   R2 is selected from:        -   a hydrogen atom, a halogen atom, or a (C₁-C₆)alkyl,            (C₃-C₇)cycloalkyl or (C₁-C₆)alkoxy group;        -   a heterocycloalkyl, heterocycloalkyl-CH₂— or heteroaryl            group;            -   wherein each said heterocycloalkyl,                heterocycloalkyl-CH₂— and heteroaryl group is optionally                substituted with one or several substituents selected,                independently in each instance, from: (C₁-C₆)alkyl,                (C₃-C₇)cycloalkyl, (C₁-C₆)alkoxy, heterocycloalkyl,                carboxy(C₁-C₆)alkyl, NR4R5 and OR4;            -   said (C₁-C₆)alkyl group being optionally substituted                with a halogen atom or a (C₁-C₆)alkoxy,                heterocycloalkyl, NH₂ or OH group; and                -   R4 and R5 being each, independently of one another,                    a hydrogen atom, a (C₁-C₆)alkyl group or a                    heterocycloalkyl group;                -   or else R4 and R5 together form, with the nitrogen                    atom which bears them, a 4- to 7-membered ring;        -   an NRaRb group, where Ra and Rb are, independently of one            another:            -   a hydrogen atom;            -   a heterocycloalkyl group, said heterocycloalkyl group                being optionally substituted with a (C₁-C₆)alkyl group;                or            -   a (C₁-C₆)alkyl group, said alkyl group being optionally                substituted with an NR4R5 group;                -   R4 and R5 being each, independently of one another,                    a hydrogen atom, a (C₁-C₆)alkyl group or a                    heterocycloalkyl group;                -   or else R4 and R5 together form, with the nitrogen                    atom which bears them, a 4- to 7-membered ring;    -   R3 is a hydrogen atom, a halogen atom or a (C₁-C₆)alkyl group;    -   wherein when R is a phenyl group, two adjacent substituents on        the phenyl group may together form a heterocycloalkyl ring fused        with the phenyl bearing them, this heterocycloalkyl being        optionally substituted with one or several substituents        selected, independently in each instance, from: an oxo group and        a (C₁-C₆)alkyl group;    -   R7 is an aryl group or heteroaryl group, this group being        optionally substituted with one or several substituents        selected, independently in each instance, from: cyano, halogen,        (C₁-C₆)alkyl, OR′4, CH₂OH, CH₂NH₂, S(O)_(n)R′4, R8 and OR8;        -   wherein:        -   R′4 is a hydrogen atom or a (C₁-C₆)alkyl or aryl group, said            alkyl and aryl groups being optionally substituted with a            halogen atom or an NH₂ or OH group;        -   n is 1 or 2; and        -   R8 is a halo(C₁-C₆)alkyl group.

In the compounds of general formula (I), the nitrogen atom(s) canoptionally be in oxidized form (N-oxide).

The present invention also relates to compounds of formula (I′):

in which:R is a phenyl or heteroaryl group substituted with R1, R′1, R2 and R3;R1 is a hydrogen atom or is selected from the following groups:(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl and aryl, these groupsbeing optionally substituted with one or several substituents selected,independently in each instance, from: amino, hydroxyl, thiol, halogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkylamino,aryloxy, aryl(C₁-C₆)alkoxy, cyano, halo(C₁-C₆)alkyl, carboxyl andcarboxy(C₁-C₆)alkyl;R′1 is a hydrogen atom or a (C₁-C₆)alkoxy group;R2 is selected from:

-   -   a hydrogen atom, a halogen atom, or a (C₁-C₆)alkyl,        (C₃-C₇)cycloalkyl or (C₁-C₆)alkoxy group;    -   a heterocycloalkyl, heterocycloalkyl-CH₂— or heteroaryl group;        wherein each said heterocycloalkyl, heterocycloalkyl-CH₂— and        heteroaryl group is optionally substituted with one or several        substituents selected, independently in each instance, from:        (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₆)alkoxy,        heterocycloalkyl, carboxy(C₁-C₆)alkyl, NR4R5 and OR4;        said (C₁-C₆)alkyl group being optionally substituted with a        halogen atom or a (C₁-C₆)alkoxy, heterocycloalkyl, NH₂ or OH        group; and    -   an NRaRb group, where Ra and Rb are, independently of one        another:    -   a hydrogen atom;    -   a heterocycloalkyl group, said heterocycloalkyl group being        optionally substituted with a (C₁-C₆)alkyl group; or    -   a (C₁-C₆)alkyl group, said alkyl group being optionally        substituted with an NR4R5 group;        R4 and R5 being, independently of one another, a hydrogen atom,        a (C₁-C₆)alkyl group or a heterocycloalkyl group;        or else R4 and R5 together form, with the nitrogen atom which        bears them, a 4- to 7-membered ring;        R3 is a hydrogen atom, a halogen atom or a (C₁-C₆)alkyl group;        wherein when R is a phenyl group, two adjacent substituents on        the phenyl group may together form a heterocycloalkyl ring fused        with the phenyl bearing them, this heterocycloalkyl being        optionally substituted with one or several substituents        selected, independently in each instance, from: an oxo group and        a (C₁-C₆)alkyl group;        R7 is an aryl or heteroaryl group, this group being optionally        substituted with one or several substituents selected,        independently in each instance, from: cyano, halogen,        (C₁-C₆)alkyl, OR′4, CH₂OH, CH₂NH₂, S(O)_(n)R′4, R8 and OR8;    -   wherein:    -   R′4 is a hydrogen atom or a (C₁-C₆)alkyl or aryl group; said        alkyl and aryl groups being optionally substituted with a        halogen atom or an NH₂ or OH group;    -   n is 1 or 2;    -   R8 is a halo(C₁-C₆)alkyl group.

The present invention also relates to compounds of formula (I″):

in which:R_(α) and R_(β) are, independently of one another, a hydrogen atom or a(C₁-C₆)alkyl group; orR_(α) and R_(β) can together form, with the carbon atom bearing them, a3- to 5-membered carbocycle;R is a phenyl or heteroaryl group substituted with R1, R′1, R2 and R3;R1 is a hydrogen atom or is selected from the following groups:(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl and aryl, these groupsbeing optionally substituted with one or several substituents selected,independently in each instance, from: amino, hydroxyl, thiol, halogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkylamino,aryloxy, aryl(C₁-C₆)alkoxy, cyano, halo(C₁-C₆)alkyl, carboxyl andcarboxy(C₁-C₆)alkyl;R′1 represents a hydrogen atom or a (C₁-C₆)alkoxy group;R2 is selected from:

-   -   a hydrogen atom, a halogen atom, or a (C₁-C₆)alkyl,        (C₃-C₇)cycloalkyl or (C₁-C₆)alkoxy group;    -   a heterocycloalkyl, heterocycloalkyl-CH₂— or heteroaryl group;        wherein each said heterocycloalkyl, heterocycloalkyl-CH₂— and        heteroaryl group is optionally substituted with one or several        substituents selected, independently in each instance, from:        (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₆)alkoxy,        heterocycloalkyl, carboxy(C₁-C₆)alkyl, NR4R5 and OR4;        said alkyl group being optionally substituted with a halogen        atom or a (C₁-C₆)alkoxy, heterocycloalkyl, NH₂ or OH group; and    -   an NRaRb group, where Ra and Rb are, independently of one        another:    -   a hydrogen atom;    -   a heterocycloalkyl group, said heterocycloalkyl group being        optionally substituted with a (C₁-C₆)alkyl group; or    -   a (C₁-C₆)alkyl group, said alkyl group being optionally        substituted with an NR4R5 group;        -   wherein:        -   R4 and R5 each is, independently of one another, a hydrogen            atom, a (C₁-C₆)alkyl group or a heterocycloalkyl group;        -   or else R4 and R5 together form, with the nitrogen atom            which bears them, a 4- to 7-membered ring;            R3 is a hydrogen atom, a halogen atom or a (C₁-C₆)alkyl            group;    -   wherein when R is a phenyl group, two adjacent substituents on        the phenyl group may together form a heterocycloalkyl ring fused        with the phenyl bearing them, this heterocycloalkyl being        optionally substituted with one or several substituents        selected, independently in each instance, from: an oxo group and        a (C₁-C₆)alkyl group;        R7 is an aryl group or heteroaryl group, this group being        optionally substituted with one or several substituents        selected, independently in each instance, from: cyano, halogen,        (C₁-C₆)alkyl, OR′4, CH₂OH, CH₂NH₂, S(O)_(n)R′4, R8 and OR8;    -   wherein:    -   R′4 is a hydrogen atom or a (C₁-C₆)alkyl or aryl group, said        alkyl and aryl groups being optionally substituted with a        halogen atom or an NH₂ or OH group;    -   n is 1 or 2;    -   is R8 is a halo(C₁-C₆)alkyl group.

Also within the present invention are the precursors (prodrugs) of thecompounds of formula (I).

The compounds of formula (I), (I′) or (I″) can comprise one or moreasymmetric carbon atoms. They can therefore exist in the form ofenantiomers or of diastereoisomers. These enantiomers anddiastereoisomers, and also mixtures thereof, including racemic mixtures,form part of the invention.

The compounds of formula (I), (I′) or (I″) can exist in the form ofbases or of addition salts with acids. Such addition salts form part ofthe invention.

The compounds of formula (I), (I′) or (I″) can exist in the form ofpharmaceutically acceptable salts.

These salts can be prepared with pharmaceutically acceptable acids, butthe salts of other acids that are of use, for example, for purifying orisolating the compounds of formula (I), (I′) or (I″) also form part ofthe invention.

In the context of the present invention:

-   -   the expression “C_(t)-C_(z) where t and z can take the values        from 1 to 7” means a carbon-based chain which can have from t to        z carbon atoms, for example C₁-C₃ means a carbon-based chain        which can have from 1 to 3 carbon atoms;    -   the term “a halogen atom” means: a fluorine, a chlorine, a        bromine or an iodine;    -   the term “an alkyl group” means: a linear or branched,        saturated, hydrocarbon-based aliphatic group comprising, unless        otherwise mentioned, from 1 to 12 carbon atoms. By way of        examples, mention may be made of methyl, ethyl, n-propyl,        isopropyl, butyl, isobutyl, tert-butyl or pentyl groups;    -   the term “a cycloalkyl group” means: a cyclic carbon-based group        comprising, unless otherwise mentioned, from 3 to 6 carbon        atoms. By way of examples, mention may be made of cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, etc. groups;    -   the term “a haloalkyl group” means: an alkyl group as defined        above, in which one or more of the hydrogen atoms is (are)        replaced with a halogen atom. By way of example, mention may be        made of fluoroalkyls, in particular CF₃ or CHF₂;    -   the term “an alkoxy group” means: an —O-alkyl radical where the        alkyl group is as previously defined. By way of examples,        mention may be made of —O—(C₁-C₄)alkyl groups, and in particular        the —O-methyl group, the —O-ethyl group as —O—C₃alkyl group, the        —O-propyl group, the —O-isopropyl group, and as —O—C₄alkyl        group, the —O-butyl, —O-isobutyl or —O-tert-butyl group;    -   the term “aryl group” means: a cyclic aromatic group comprising        between 6 and 10 carbon atoms. By way of examples of aryl        groups, mention may be made of phenyl or naphthyl groups;    -   the term “a heteroaryl” means: a 5- to 10-membered aromatic        monocyclic or bicyclic group containing from 1 to 4 heteroatoms        selected from O, S or N. By way of examples, mention may be made        of imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl,        pyrazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrazinyl,        pyrimidinyl, pyridazinyl, indolyl, benzofuranyl,        benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl,        benzothiazolyl, isobenzothiazolyl, benzotriazolyl, quinolinyl        and isoquinolinyl groups;        by way of a heteroaryl comprising 5 to 6 atoms, including 1 to 4        nitrogen atoms, mention may in particular be made of the        following representative groups: pyrrolyl, pyrazolyl,        1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl and        1,2,3-triazinyl;        Mention may also be made, by way of heteroaryl, of thiophenyl,        oxazolyl, furazanyl, 1,2,4-thiadiazolyl, naphthyridinyl,        quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine,        imidazo[2,1-b]thiazolyl, cinnolinyl, benzofurazanyl, azaindolyl,        benzimidazolyl, benzothiophenyl, thienopyridyl,        thienopyrimidinyl, pyrrolopyridyl, imidazopyridyl,        benzoazaindole, 1,2,4-triazinyl, indolizinyl, isoxazolyl,        isoquinolinyl, isothiazolyl, purinyl, quinazolinyl, quinolinyl,        isoquinolyl, 1,3,4-thiadiazolyl, thiazolyl, isothiazolyl,        carbazolyl, and also the corresponding groups resulting from        their fusion or from fusion with the phenyl nucleus;    -   the term “a heterocycloalkyl” means: a 4- to 10-membered,        saturated or partially unsaturated, monocyclic or bicyclic group        comprising from one to three heteroatoms selected from O, S or        N; the heterocycloalkyl group may be attached to the rest of the        molecule via a carbon atom or via a heteroatom; the term        bicyclic heterocycloalkyl includes fused bicycles and spiro-type        rings.

By way of saturated heterocycloalkyl comprising from 5 to 6 atoms,mention may be made of oxetanyl, tetrahydrofuranyl, dioxolanyl,pyrrolidinyl, azepinyl, oxazepinyl, pyrazolidinyl, imidazolidinyl,tetrahydrothiophenyl, dithiolanyl, thiazolidinyl, tetrahydropyranyl,tetrahydropyridinyl, dioxanyl, morpholinyl, piperidinyl, piperazinyl,tetrahydrothiopyranyl, dithianyl, thiomorpholinyl or isoxazolidinyl.

Among the heterocycloalkyls, mention may also be made, by way ofexamples, of bicyclic groups such as(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, octahydroindozilinyl,diazepanyl, dihydroimidazopyrazinyl and diazabicycloheptanyl groups, orelse diazaspiro rings such as 1,7-diazaspiro[4.4]non-7-yl or1-ethyl-1,7-diazaspiro[4.4]non-7-yl.

When the heterocycloalkyl is substituted, the substitution(s) may be onone (or more) carbon atom(s) and/or on the heteroatom(s). When theheterocycloalkyl comprises several substituents, they may be borne byone and the same atom or different atoms.

The abovementioned “alkyl”, “cycloalkyl”, “aryl”, “heteroaryl” and“heterocycloalkyl” radicals can be substituted with one or moresubstituents. Among these substituents, mention may be made of thefollowing groups: amino, hydroxyl, thiol, oxo, halogen, alkyl, alkoxy,alkylthio, alkylamino, aryloxy, arylalkoxy, cyano, trifluoromethyl,carboxy or carboxyalkyl;

-   -   the term “an alkylthio” means: an —S-alkyl group, the alkyl        group being as defined above;    -   the term “an alkylamino” means: an —NH-alkyl group, the alkyl        group being as defined above;    -   the term “an aryloxy” means: an —O-aryl group, the aryl group        being as defined above;    -   the term “an arylalkoxy” means: an aryl-alkoxy- group, the aryl        and alkoxy groups being as defined above;    -   the term “a carboxyalkyl” means: an HOOC-alkyl- group, the alkyl        group being as defined above. As examples of carboxyalkyl        groups, mention may in particular be made of carboxymethyl or        carboxyethyl;    -   the term “a carboxyl” means: a COOH group;    -   the term “an oxo” means: “═O”.

When an alkyl radical is substituted with an aryl group, the term“arylalkyl” or “aralkyl” radical is used. The “arylalkyl” or “aralkyl”radicals are aryl-alkyl- radicals, the aryl and alkyl groups being asdefined above. Among the arylalkyl radicals, mention may in particularbe made of the benzyl or phenethyl radicals.

Subgroup 1 is defined by the compounds of formula (I) for which:

R6 is —CONH₂ or a —C(R_(α))(R_(β))(OH) group in which R_(α) and R_(β)are, independently of one another, a hydrogen atom or a (C₁-C₆)alkylgroup.

Subgroup 2 is defined by the compounds of formula (I) for which:

R6 is —CONH₂, —CH₂OH or C(CH₃)₂OH.

Subgroup 3 is defined by the compounds of formula (I) for which:

R is a phenyl, pyridinyl or pyrazolyl group substituted with R1, R′1, R2and R3; R1, R′1, R2 and R3 being as defined in formula (I).

Subgroup 4 is defined by the compounds of formula (I) for which:

R is selected from the following groups:

R1, R′1, R2 and R3 being as defined in formula (I).

Subgroup 5 is defined by the compounds of formula (I) for which:

R is an (A), (E) or (F) group

R1, R′1, R2 and R3 being as defined in formula (I).

Subgroup 6 is defined by the compounds of formula (I) for which:

R is an (A) group

R1, R′1, R2 and R3 being as defined in formula (I).

Subgroup 7 is defined by the compounds of formula (I) for which:

R1 is a hydrogen atom or is selected from the following groups:(C₁-C₆)alkyl, such as methyl or isopropyl, (C₁-C₆)alkoxy, such asmethoxy or isopropyloxy, (C₃-C₇)cycloalkyl, such as cyclobutyl, andaryl, such as phenyl.

Subgroup 8 is defined by the compounds of formula (I) for which:

R1 is an isopropyloxy group.

Subgroup 9 is defined by the compounds of formula (I) for which:

R′1 is an hydrogen atom or an isopropyloxy group.

Subgroup 10 is defined by the compounds of formula (I) for which:

R′1 is a hydrogen atom.

Subgroup 11 is defined by the compounds of formula (I) for which:

R2 is selected from:

-   -   a hydrogen or chlorine atom, or a methyl, cyclopropyl or methoxy        group;    -   a pyrrolidinyl, piperidinyl, tetrahydropyridinyl, piperazinyl,        tetrahydropyranyl, 1,4-diazepan-1-yl, diazabicycloheptanyl,        (8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,        1,7-diazaspiro[4.4]non-7-yl, octahydroindolizinyl,        dihydroimidazopyrazinyl, piperazinyl-CH₂, pyrazolyl, imidazolyl,        triazolyl or pyridinyl group;        these groups being optionally substituted with one or more        substituents selected, independently in each instance, from:        (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₆)alkoxy,        heterocycloalkyl, carboxy(C₁-C₆)alkyl, NR4R5 and OR4;    -   said (C₁-C₆)alkyl group being optionally substituted with a        halogen atom or a (C₁-C₆)alkoxy, heterocycloalkyl, NH₂ or OH        group; and        -   R4 and R5 each is, independently of one another, a hydrogen            atom, a (C₁-C₆)alkyl group, such as methyl or ethyl, or a            heterocycloalkyl group, such as oxetanyl;        -   or else R4 and R5 together form, with the nitrogen atom            which bears them, a 4- to 7-membered ring, such as            pyrrolidinyl;    -   an NRaRb group, where Ra and Rb are, independently of one        another:    -   a hydrogen atom;    -   a piperidinyl group or tetrahydropyranyl group, wherein each of        said piperidinyl and tetrahydropyranyl groups is independently        optionally substituted with a (C₁-C₆)alkyl group, such as        methyl; or    -   a methyl or ethyl group, said group being optionally substituted        with an NR4R5 group;        -   wherein:        -   R4 and R5 each is, independently of one another, a hydrogen            atom, a (C₁-C₆)alkyl group, such as methyl or ethyl, or a            heterocycloalkyl group, such as oxetanyl;        -   or else R4 and R5 together form, with the nitrogen atom            which bears them, a 4- to 7-membered ring, such as            pyrrolidinyl;            R3 is a hydrogen atom, a halogen atom, such as a fluorine,            or a (C₁-C₆)alkyl group, such as a methyl;            and when R corresponds to formula (A), R2 and R3 can            together form an azepinyl or oxazepinyl ring fused with the            phenyl bearing them, this azepinyl or oxazepinyl being            optionally substituted with one or more substituents            selected, independently in each instance, from: an oxo group            and a (C₁-C₆)alkyl group, such as methyl.

Subgroup 12 is defined by the compounds of formula (I) for which:

R2 is a pyrrolidinyl, piperidinyl, tetrahydropyridinyl, piperazinyl,tetrahydropyranyl, 1,4-diazepan-1-yl, diazabicycloheptanyl,(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,1,7-diazaspiro[4.4]non-7-yl, octahydroindolizinyl,dihydroimidazopyrazinyl, piperazinyl-CH₂, pyrazolyl, imidazolyl,triazolyl or pyridinyl group;these groups being optionally substituted with at least one substituentselected from: (C₁-C₆)alkyl, such as methyl, ethyl or isopropyl,(C₃-C₇)cycloalkyl, such as cyclopropyl, (C₁-C₆)alkoxy, such as methoxy,heterocycloalkyl, such as oxetanyl or pyrrolidinyl, carboxy(C₁-C₆)alkyl,such as C(O)O(CH₃)₃, NR4R5 and OH;said alkyl group being optionally substituted with a (C₁-C₆)alkoxygroup, such as methoxy, or OH;R4 and R5 being, independently of one another, a hydrogen atom, a(C₁-C₆)alkyl group, such as methyl or ethyl, or a heterocycloalkylgroup, such as oxetanyl;or else R4 and R5 together form, with the nitrogen atom which bearsthem, a 4- to 7-membered ring, such as pyrrolidinyl;R3 is a hydrogen atom, a halogen atom, such as a fluorine, or a(C₁-C₆)alkyl group, such as a methyl.

Subgroup 13 is defined by the compounds of formula (I) for which:

R2 is a piperidinyl or piperazinyl group, these groups being optionallysubstituted with at least one substituent selected from: (C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₁-C₆)alkoxy, heterocycloalkyl, carboxy(C₁-C₆)alkyl,NR4R5 and OR4;said alkyl group being optionally substituted with a halogen atom or a(C₁-C₆)alkoxy, heterocycloalkyl, NH₂ or OH group;R4 and R5 being as defined in formula (I);R3 is a hydrogen atom, a halogen atom, such as a fluorine, or a(C₁-C₆)alkyl group, such as a methyl.

Subgroup 14 is defined by the compounds of formula (I) for which:

R2 is a piperidinyl or piperazinyl group, these groups being optionallysubstituted with at least one substituent selected from: a methyl,ethyl, isopropyl, cyclopropyl, OH, oxetanyl, pyrrolidinyl, C(O)O(CH₃)₃,NR4R5 and OR4 group;said methyl, ethyl and isopropyl groups being optionally substitutedwith a (C₁-C₆)alkoxy group, such as methoxy, or with an OH;R4 and R5 being, independently of one another, a hydrogen atom, a(C₁-C₆)alkyl group, such as methyl, or a heterocycloalkyl group, such asoxetanyl;R3 is a hydrogen or fluorine atom or a methyl.

Subgroup 15 is defined by the compounds of formula (I) for which:

R2 is a piperidinyl or piperazinyl group, these groups being optionallysubstituted with at least one substituent selected from: a methyl, ethylor isopropyl group:R3 is a hydrogen or fluorine atom or a methyl.

Subgroup 16 is defined by the compounds of formula (I) for which:

R2 is a group selected from the following groups:

R3 is a hydrogen or fluorine atom or a methyl.

Subgroup 17 is defined by the compounds of formula (I) for which:

R7 is a phenyl, pyridinyl, thienyl, furanyl, pyrazolyl or pyrolyl group,this group being optionally substituted with one or more substituentsselected, independently in each instance, from: cyano, halogen,(C₁-C₆)alkyl, OR′4, CH₂OH, CH₂NH₂, S(O)_(n)R′4, R8 and OR8;

-   -   wherein:        -   R′4 is a hydrogen atom or a (C₁-C₆)alkyl or aryl group, said            alkyl and aryl groups being optionally substituted with a            halogen atom or an NH₂ or OH group;        -   n is 1 or 2;        -   R8 is a halo(C₁-C₆)alkyl group.

Subgroup 18 is defined by the compounds of formula (I) for which:

R7 is a phenyl, pyridinyl, thienyl, furanyl, pyrazolyl or pyrolyl group,this group being optionally substituted with one or more substituentsindependently selected from:cyano, halogen, such as chlorine or fluorine, (C₁-C₆)alkyl, such asmethyl, OR′4, CH₂OH, CH₂NH₂, S(O)_(n)R′4 and OR8;

-   -   wherein:    -   R′4 is a (C₁-C₆)alkyl group, such as methyl or ethyl;    -   n is 1;    -   R8 is a halo(C₁-C₆)alkyl group, such as CF₃ or CHF₂.

Subgroup 19 is defined by the compounds of formula (I) for which R, R6and R7 are defined in one of subgroups 1 to 18 above.

Subgroup 20 is defined by the compounds of formula (I) for which:

R6 is —CONH₂ or a —C(R_(α))(R_(β))(OH) group in which R_(α) and R_(β)are, independently of one another, a hydrogen atom or a (C₁-C₆)alkylgroup;R is a phenyl, pyridinyl or pyrazolyl group substituted with R1, R′1, R2and R3;R1 is a hydrogen atom or is selected from the following groups:(C₁-C₆)alkyl, such as methyl or isopropyl, (C₁-C₆)alkoxy, such asmethoxy or isopropyloxy, (C₃-C₇)cycloalkyl, such as cyclobutyl, andaryl, such as phenyl;R′1 is a hydrogen atom or an isopropyloxy group;R2 is selected from:

-   -   a hydrogen or chlorine atom or a methyl, cyclopropyl or methoxy        group:        -   a pyrrolidinyl, piperidinyl, tetrahydropyridinyl,            piperazinyl, tetrahydropyranyl, 1,4-diazepan-1-yl,            diazabicycloheptanyl,            (8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,            1,7-diazaspiro[4.4]non-7-yl, octahydroindolizinyl,            dihydroimidazopyrazinyl, piperazinyl-CH₂, pyrazolyl,            imidazolyl, triazolyl or pyridinyl group;            these groups being optionally substituted with one or more            substituents independently selected from: (C₁-C₆)alkyl,            (C₃-C₇)cycloalkyl, (C₁-C₆)alkoxy, heterocycloalkyl,            carboxy(C₁-C₆)alkyl, NR4R5 and OR4;    -   said alkyl group being optionally substituted with a halogen        atom or a (C₁-C₆)alkoxy, heterocycloalkyl, NH₂ or OH group; and    -   an NRaRb group, where Ra and Rb are, independently of one        another:    -   a hydrogen atom;    -   a piperidinyl or tetrahydropyranyl group, said group being        optionally substituted with a (C₁-C₆)alkyl group, such as        methyl; or    -   a methyl or ethyl group, said group being optionally substituted        with an NR4R5 group;        R4 and R5 being, independently of one another, a hydrogen atom,        a (C₁-C₆)alkyl group, such as methyl or ethyl, or a        heterocycloalkyl group, such as oxetanyl;        or else R4 and R5 together form, with the nitrogen atom which        bears them, a 4- to 7-membered ring, such as a pyrrolidinyl;        R3 is a hydrogen atom, a halogen atom, such as a fluorine, or a        (C₁-C₆)alkyl group, such as a methyl;        wherein when R corresponds to formula (A), R2 and R3 may        together form an azepinyl or oxazepinyl ring fused with the        phenyl bearing them, this azepinyl or oxazepinyl ring being        optionally substituted with at least one substituent selected        from: an oxo group and a (C₁-C₆)alkyl group;        R7 is a phenyl, pyridinyl, thienyl, furanyl, pyrazolyl or        pyrolyl group, this group being optionally substituted with one        or more substituents selected, independently in each instance,        from: cyano, halogen, (C₁-C₆)alkyl, OR′4, CH₂OH, CH₂NH₂,        S(O)_(n)R′4, R8 and OR8;    -   wherein:    -   R′4 is a hydrogen atom or a (C₁-C₆)alkyl or aryl group, said        alkyl and aryl groups being optionally substituted with a        halogen atom or an NH₂ or OH group;    -   n is 1 or 2; and    -   R8 is a halo(C₁-C₆)alkyl group.

Subgroup 21 is defined by the compounds of formula (I) for which:

R6 is —CONH₂ or a —C(R_(α))(R_(β))(OH) group in which R_(α) and R_(β)are, independently of one another, a hydrogen atom or a (C₁-C₆)alkylgroup;R is selected from the following groups:

R1 is a hydrogen atom or is selected from the following groups:(C₁-C₆)alkyl, such as methyl or isopropyl, (C₁-C₆)alkoxy, such asmethoxy or isopropyloxy, (C₃-C₇)cycloalkyl, such as cyclobutyl, andaryl, such as phenyl;R′1 is a hydrogen atom or an isopropyloxy group;R2 is a pyrrolidinyl, piperidinyl, tetrahydropyridinyl, piperazinyl,tetrahydropyranyl, 1,4-diazepan-1-yl, diazabicycloheptanyl,(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,1,7-diazaspiro[4.4]non-7-yl, octahydroindolizinyl,dihydroimidazopyrazinyl, piperazinyl-CH₂, pyrazolyl, imidazolyl,triazolyl or pyridinyl group;these groups being optionally substituted with one or more substituentsselected, independently in each instance, from: (C₁-C₆)alkyl, such asmethyl, ethyl or isopropyl, (C₃-C₇)cycloalkyl, such as cyclopropyl,(C₁-C₆)alkoxy, such as methoxy, heterocycloalkyl, such as oxetanyl orpyrrolidinyl, carboxy(C₁-C₆)alkyl, such as C(O)O(CH₃)₃, NR4R5 and OH;

-   -   said (C₁-C₆)alkyl group being optionally substituted with a        (C₁-C₆)alkoxy group, such as methoxy, or OH;        -   wherein:            -   R4 and R5 each is, independently of one another, a                hydrogen atom, a (C₁-C₆)alkyl group or a                heterocycloalkyl group;            -   or else R4 and R5 together form, with the nitrogen atom                which bears them, a 4- to 7-membered ring;                R3 is a hydrogen atom, a halogen atom, such as a                fluorine, or a (C₁-C₆)alkyl group, such as a methyl;                R7 is a phenyl, pyridinyl, thienyl, furanyl, pyrazolyl                or pyrolyl group, this group being optionally                substituted with one or more substituents selected,                independently in each instance, from: cyano, halogen,                (C₁-C₆)alkyl, OR′4, CH₂OH, CH₂NH₂, S(O)_(n)R′4, R8 and                OR8;    -   wherein:    -   R′4 is a hydrogen atom or a (C₁-C₆)alkyl or aryl group, said        alkyl and aryl groups being optionally substituted with a        halogen atom or an NH₂ or OH group;    -   n 1 or 2; and    -   R8 is a halo(C₁-C₆)alkyl group.

Subgroup 22 is defined by the compounds of formula (I) for which:

R6 is —CONH₂ or a —C(R_(α))(R_(β))(OH) group in which R_(α) and R_(β)are, independently of one another, a hydrogen atom or a (C₁-C₆)alkylgroup;R is an (A), (E) or (F) group

R1 is an isopropyloxy group;R′1 is a hydrogen atom;R2 is a piperidinyl or piperazinyl group, these groups being optionallysubstituted with one or more substituents selected, independently ineach instance, from: a methyl, ethyl, isopropyl, cyclopropyl, OH,oxetanyl, pyrrolidinyl, C(O)O(CH₃)₃, NR4R5 and OR4 group;

-   -   said methyl, ethyl and isopropyl groups being optionally        substituted with a (C₁-C₆)alkoxy group, such as methoxy, or with        an OH;        -   wherein R4 and R5 each is, independently of one another, a            hydrogen atom, a (C₁-C₆)alkyl group, such as methyl, or a            heterocycloalkyl group, such as oxetanyl;            R3 is a hydrogen or fluorine atom or a methyl;            R7 is a phenyl, pyridinyl, thienyl, furanyl, pyrazolyl or            pyrolyl group, this group being optionally substituted with            one or more substituents selected, independently in each            instance, from: cyano, halogen, such as chlorine or            fluorine, (C₁-C₆)alkyl, such as methyl, OR′4, CH₂OH, CH₂NH₂,            S(O)_(n)R′4 and OR8;    -   wherein:    -   R′4 is a (C₁-C₆)alkyl group, such as methyl or ethyl;    -   n is 1; and    -   R8 is a halo(C₁-C₆)alkyl group, such as CF₃ or CHF₂.

Subgroup 23 is defined by the compounds of formula (I′) for which:

R is a phenyl, pyridinyl or pyrazolyl group substituted with R1, R′1, R2and R3; R1, R′1, R2 and R3 being as defined in formula (I′).

Subgroup 24 is defined by the compounds of formula (I′) for which:

R is selected from the following groups:

R1, R′1, R2 and R3 being as defined in formula (I′).

Subgroup 25 is defined by the compounds of formula (I′) for which:

R is an (A), (E) or (F) group

R1, R′1, R2 and R3 being as defined in formula (I′).

Subgroup 26 is defined by the compounds of formula (I′) for which:

R is an (A) group

R1, R′1, R2 and R3 being as defined in formula (I′).

Subgroup 27 is defined by the compounds of formula (I′) for which:

R1 is a hydrogen atom or is selected from the following groups:(C₁-C₆)alkyl, such as methyl or isopropyl, (C₁-C₆)alkoxy, such asmethoxy or isopropyloxy, (C₃-C₇)cycloalkyl, such as cyclobutyl, andaryl, such as phenyl.

Subgroup 28 is defined by the compounds of formula (I′) for which:

R1 is an isopropyloxy group.

Subgroup 29 is defined by the compounds of formula (I′) for which:

R′1 is a hydrogen atom or an isopropyloxy group.

Subgroup 30 is defined by the compounds of formula (I′) for which:

R′1 is a hydrogen atom.

Subgroup 31 is defined by the compounds of formula (I′) for which:

R2 is selected from:

-   -   a hydrogen atom or a methyl, cyclopropyl or methoxy group;        -   a pyrrolidinyl, piperidinyl, tetrahydropyridinyl,            piperazinyl, tetrahydropyranyl, 1,4-diazepan-1-yl,            diazabicycloheptanyl,            (8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,            1,7-diazaspiro[4.4]non-7-yl, octahydroindolizinyl,            dihydroimidazopyrazinyl, piperazinyl-CH₂, pyrazolyl,            imidazolyl, triazolyl or pyridinyl group;            these groups being optionally substituted with one or            several substituents independently selected from:            (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₆)alkoxy,            heterocycloalkyl, carboxy(C₁-C₆)alkyl, NR4R5 and OR4;            said alkyl group being optionally substituted with a halogen            atom or a (C₁-C₆)alkoxy, heterocycloalkyl, NH₂ or OH group;            and    -   an NRaRb group, where Ra and Rb are, independently of one        another:    -   a hydrogen atom;    -   a piperidinyl or tetrahydropyranyl group, said group being        optionally substituted with a (C₁-C₆)alkyl group, such as        methyl; or        -   a methyl or ethyl group, said alkyl group being optionally            substituted with an NR4R5 group;            R4 and R5 being, independently of one another, a hydrogen            atom, a (C₁-C₆)alkyl group, such as methyl or ethyl, or a            heterocycloalkyl group, such as oxetanyl;            or else R4 and R5 together form, with the nitrogen atom            which bears them, a 4- to 7-membered ring, such as a            pyrrolidinyl;            R3 is a hydrogen atom, a halogen atom, such as a fluorine,            or a (C₁-C₆)alkyl group, such as a methyl;            and when R corresponds to formula (A), R2 and R3 can            together form an azepinyl or oxazepinyl ring, fused with the            phenyl bearing them, this azepinyl or oxazepinyl ring being            optionally substituted with at least one substituent            selected from: an oxo group and a (C₁-C₆)alkyl group, such            as methyl.

Subgroup 32 is defined by the compounds of formula (I′) for which:

R2 is a pyrrolidinyl, piperidinyl, tetrahydropyridinyl, piperazinyl,tetrahydropyranyl, 1,4-diazepan-1-yl, diazabicycloheptanyl,(8aR)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,1,7-diazaspiro[4.4]non-7-yl, octahydroindolizinyl,dihydroimidazopyrazinyl, piperazinyl-CH₂, pyrazolyl, imidazolyl,triazolyl or pyridinyl group;these groups being optionally substituted with one or severalsubstituents independently selected from: (C₁-C₆)alkyl, such as methyl,ethyl or isopropyl, (C₃-C₇)cycloalkyl, such as cyclopropyl,(C₁-C₆)alkoxy, such as methoxy, heterocycloalkyl, such as oxetanyl orpyrrolidinyl, carboxy(C₁-C₆)alkyl, such as C(O)O(CH₃)₃, NR4R5 and OH;said alkyl group being optionally substituted with a (C₁-C₆)alkoxygroup, such as methoxy, or OH;R4 and R5 being, independently of one another, a hydrogen atom, a(C₁-C₆)alkyl group, such as methyl or ethyl, or a heterocycloalkylgroup, such as oxetanyl;or else R4 and R5 together form, with the nitrogen atom which bearsthem, a 4- to 7-membered ring, such as a pyrrolidinyl;R3 is a hydrogen atom, a halogen atom, such as a fluorine, or a(C₁-C₆)alkyl group, such as a methyl.

Subgroup 33 is defined by the compounds of formula (I′) for which:

R2 is a piperidinyl or piperazinyl group, these groups being optionallysubstituted with one or several substituents independently selectedfrom: (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₆)alkoxy, heterocycloalkyl,carboxy(C₁-C₆)alkyl, NR4R5 and OR4;said alkyl group being optionally substituted with a halogen atom or a(C₁-C₆)alkoxy, heterocycloalkyl, NH₂ or OH group;R4 and R5 being as defined in formula (I);R3 is a hydrogen atom, a halogen atom, such as a fluorine, or a(C₁-C₆)alkyl group, such as a methyl.

Subgroup 34 is defined by the compounds of formula (I′) for which:

R2 represents a piperidinyl or piperazinyl group, these groups beingoptionally substituted with one or several substituents independentlyselected from: a methyl, ethyl, isopropyl, cyclopropyl, OH, oxetanyl,pyrrolidinyl, C(O)O(CH₃)₃, NR4R5 and OR4 group;said alkyl group being optionally substituted with a (C₁-C₆)alkoxygroup, such as methoxy, or with an OH;R4 and R5 being, independently of one another, a hydrogen atom, a(C₁-C₆)alkyl group, such as methyl, or a heterocycloalkyl group, such asoxetanyl;R3 is a hydrogen or fluorine atom or a methyl.

Subgroup 35 is defined by the compounds of formula (I′) for which:

R2 is a piperidinyl group or piperazinyl group, these piperidinyl orpiperazinyl groups being optionally substituted with one or moresubstituents selected, independently in each instance, from: a methyl,ethyl or isopropyl group;R3 is a hydrogen or fluorine atom or a methyl.

Subgroup 36 is defined by the compounds of formula (I′) for which:

R2 is a group selected from the following groups:

R3 is a hydrogen or fluorine atom or a methyl.

Subgroup 37 is defined by the compounds of formula (I′) for which:

R7 is a phenyl, pyridinyl, thienyl, furanyl, pyrazolyl or pyrolyl group,this group being optionally substituted with one or more substituentsselected, independently in each instance, from: cyano, halogen,(C₁-C₆)alkyl, OR′4, CH₂OH, CH₂NH₂, S(O)_(n)R′4, R8 and OR8;

-   -   wherein:    -   R′4 is a hydrogen atom or a (C₁-C₆)alkyl or aryl group, said        alkyl and aryl groups being optionally substituted with a        halogen atom or an NH₂ or OH group;    -   n is 1 or 2; and    -   R8 is a halo(C₁-C₆)alkyl group.

Subgroup 38 is defined by the compounds of formula (I′) for which:

R7 is a phenyl, pyridinyl, thienyl, furanyl, pyrazolyl or pyrolyl group,this group being optionally substituted with one or more substituentsselected, independently in each instance, from: cyano, halogen, such aschlorine or fluorine, (C₁-C₆)alkyl, such as methyl, OR′4, CH₂OH, CH₂NH₂,S(O)_(n)R′4 and OR8;

-   -   wherein:    -   R′4 is a (C₁-C₆)alkyl group, such as methyl or ethyl;    -   n is 1;    -   R8 is a halo(C₁-C₆)alkyl group, such as CF₃ or CHF₂.

Subgroup 39 is defined by the compounds of formula (I′) for which R andR7 are defined in one of subgroups 23 to 38 above.

Subgroup 40 is defined by the compounds of formula (I′) for which:

R is a phenyl, pyridinyl or pyrazolyl group substituted with R1, R′1, R2and R3;R1 is a hydrogen atom or is selected from the following groups:(C₁-C₆)alkyl, such as methyl or isopropyl, (C₁-C₆)alkoxy, such asmethoxy or isopropyloxy, (C₃-C₇)cycloalkyl, such as cyclobutyl, andaryl, such as phenyl;R′1 is a hydrogen atom or an isopropyloxy group;R2 is selected from:

-   -   a hydrogen atom or a methyl, cyclopropyl or methoxy group;        -   a pyrrolidinyl, piperidinyl, tetrahydropyridinyl,            piperazinyl, tetrahydropyranyl, 1,4-diazepan-1-yl,            diazabicycloheptanyl,            (8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,            1,7-diazaspiro[4.4]non-7-yl, octahydroindolizinyl,            dihydroimidazopyrazinyl, piperazinyl-CH₂, pyrazolyl,            imidazolyl, triazolyl or pyridinyl group;            these groups being optionally substituted with one or more            substituents selected, independently in each instance, from:            (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₆)alkoxy,            heterocycloalkyl, carboxy(C₁-C₆)alkyl, NR4R5 and OR4;            said alkyl group being optionally substituted with a halogen            atom or a (C₁-C₆)alkoxy, heterocycloalkyl, NH₂ or OH group;            and    -   an NRaRb group, where Ra and Rb are, independently of one        another:    -   a hydrogen atom;    -   a piperidinyl or tetrahydropyranyl group, said group being        optionally substituted with a (C₁-C₆)alkyl group, such as        methyl; or    -   a methyl or ethyl group, said alkyl group being optionally        substituted with an NR4R5 group;        R4 and R5 are, independently of one another, a hydrogen atom, a        (C₁-C₆)alkyl group, such as methyl or ethyl, or a        heterocycloalkyl group, such as oxetanyl;        or else R4 and R5 together form, with the nitrogen atom which        bears them, a 4- to 7-membered ring, such as a pyrrolidinyl;        R3 is a hydrogen atom, a halogen atom, such as a fluorine, or a        (C₁-C₆)alkyl group, such as a methyl;        and when R corresponds to formula (A), R2 and R3 can together        form an azepinyl or oxazepinyl ring, fused with the phenyl        bearing them, this heterocycloalkyl being optionally substituted        with at least one substituent selected from: an oxo group and a        (C₁-C₆)alkyl group, such as methyl;        R7 is a phenyl, pyridinyl, thienyl, furanyl, pyrazolyl or        pyrolyl group, this group being optionally substituted with one        or more substituents selected, independently in each instance,        from: cyano, halogen, (C₁-C₆)alkyl, OR′4, CH₂OH, CH₂NH₂,        S(O)_(n)R′4, R8 and OR8;    -   wherein:    -   R′4 is a hydrogen atom or a (C₁-C₆)alkyl or aryl group, said        alkyl and aryl groups being optionally substituted with a        halogen atom or an NH₂ or OH group;    -   n is 1 or 2; and    -   R8 is a halo(C₁-C₆)alkyl group.

Subgroup 41 is defined by the compounds of formula (I′) for which:

R is selected from the following groups:

R1 is a hydrogen atom or is selected from the following groups:(C₁-C₆)alkyl, such as methyl or isopropyl, (C₁-C₆)alkoxy, such asmethoxy or isopropyloxy, (C₃-C₇)cycloalkyl, such as cyclobutyl, andaryl, such as phenyl;R′1 is a hydrogen atom or an isopropyloxy group;R2 is a pyrrolidinyl, piperidinyl, tetrahydropyridinyl, piperazinyl,tetrahydropyranyl, 1,4-diazepan-1-yl, diazabicycloheptanyl,(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,1,7-diazaspiro[4.4]non-7-yl, octahydroindolizinyl,dihydroimidazopyrazinyl, piperazinyl-CH₂, pyrazolyl, imidazolyl,triazolyl or pyridinyl group;these groups being optionally substituted with one or more substituentsselected, independently in each instance, from: (C₁-C₆)alkyl, such asmethyl, ethyl or isopropyl, (C₃-C₇)cycloalkyl, such as cyclopropyl,(C₁-C₆)alkoxy, such as methoxy, heterocycloalkyl, such as oxetanyl orpyrrolidinyl, carboxy(C₁-C₆)alkyl, such as C(O)O(CH₃)₃, NR4R5 and OH;said alkyl group being optionally substituted with a (C₁-C₆)alkoxygroup, such as methoxy, or OH;R4 and R5 being, independently of one another, a hydrogen atom, a(C₁-C₆)alkyl group, such as methyl or ethyl, or a heterocycloalkylgroup, such as oxetanyl;or else R4 and R5 together form, with the nitrogen atom which bearsthem, a 4- to 7-membered ring, such as a pyrrolidinyl;R3 is a hydrogen atom, a halogen atom, such as a fluorine, or a(C₁-C₆)alkyl group, such as a methyl;R7 is a phenyl, pyridinyl, thienyl, furanyl, pyrazolyl or pyrolyl group,this group being optionally substituted with one or more substituentsselected, independently in each instance, from: cyano, halogen,(C₁-C₆)alkyl, OR′4, CH₂OH, CH₂NH₂, S(O)_(n)R′4, R8 and OR8;

-   -   wherein:    -   R′4 is a hydrogen atom or a (C₁-C₆)alkyl or aryl group, said        alkyl and aryl groups being optionally substituted with a        halogen atom or an NH₂ or OH group;    -   n is 1 or 2;    -   R8 is a halo(C₁-C₆)alkyl group.

Subgroup 42 is defined by the compounds of formula (I′) for which:

R is an (A), (E) or (F) group

R1 is an isopropyloxy group;R′1 is a hydrogen atom;R2 is a piperidinyl or piperazinyl group, these groups being optionallysubstituted with one or more substituents selected, independently ineach instance, from: a methyl, ethyl, isopropyl, cyclopropyl, OH,oxetanyl, pyrrolidinyl, C(O)O(CH₃)₃, NR4R5 and OR4 group; said alkylgroup being optionally substituted with a (C₁-C₆)alkoxy group, such asmethoxy, or with an OH;R4 and R5 being, independently of one another, a hydrogen atom, a(C₁-C₆)alkyl group, such as methyl, or a heterocycloalkyl group, such asoxetanyl;R3 is a hydrogen or fluorine atom or a methyl;R7 is a phenyl, pyridinyl, thienyl, furanyl, pyrazolyl or pyrolyl group,this group being optionally substituted with one or more substituentsselected, independently in each instance, from: cyano, halogen, such aschlorine or fluorine, (C₁-C₆)alkyl, such as methyl, OR′4, CH₂OH, CH₂NH₂,S(O)_(n)R′4 and OR8;

-   -   wherein:    -   R′4 is a (C₁-C₆)alkyl group, such as methyl or ethyl;    -   n is 1;    -   R8 is a halo(C₁-C₆)alkyl group, such as CF₃ or CHF₂.

Subgroup 43 is defined by the compounds of formula (I″) for which:

R is a phenyl, pyridinyl or pyrazolyl group substituted with R1, R′1, R2and R3; R1, R′1, R2 and R3 being as defined in formula (I″).

Subgroup 44 is defined by the compounds of formula (I″) for which:

R is selected from the following groups:

R1, R′1, R2 and R3 being as defined in formula (I″).

Subgroup 45 is defined by the compounds of formula (I″) for which:

R is a an (A) group

R1, R′1, R2 and R3 being as defined in formula (I″).

Subgroup 46 is defined by the compounds of formula (I″) for which:

R1 is selected from the following groups: (C₁-C₆)alkyl, such asisopropyl, and (C₁-C₆)alkoxy, such as methoxy or isopropyloxy.

Subgroup 47 is defined by the compounds of formula (I″) for which:

R1 is an isopropyloxy group.

Subgroup 48 is defined by the compounds of formula (I″) for which:

R′1 is a hydrogen atom.

Subgroup 49 is defined by the compounds of formula (I″) for which:

R2 is selected from:

-   -   a hydrogen or chlorine atom or a methyl group;        -   a pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl,            1,7-diazaspiro[4.4]non-7-yl or pyrazolyl group;            these groups being optionally substituted with at least one            (C₁-C₆)alkyl group;            R3 is a hydrogen atom or a (C₁-C₆)alkyl group, such as a            methyl.

Subgroup 50 is defined by the compounds of formula (I″) for which:

R2 is selected from a pyrrolidinyl, piperidinyl, piperazinyl,tetrahydropyranyl, 1,7-diazaspiro[4.4]non-7-yl or pyrazolyl group;these groups being optionally substituted with at least one (C₁-C₆)alkylgroup, such as methyl;R3 is a hydrogen atom or a (C₁-C₆)alkyl group, such as a methyl.

Subgroup 51 is defined by the compounds of formula (I″) for which:

R2 is a piperidinyl or piperazinyl group, these groups being optionallysubstituted with at least one (C₁-C₆)alkyl group, such as methyl;R3 is a hydrogen atom or a (C₁-C₆)alkyl group, such as a methyl.

Subgroup 52 is defined by the compounds of formula (I″) for which:

R2 is a group selected from the following groups:

R3 is a hydrogen atom or a methyl.

Subgroup 53 is defined by the compounds of formula (I″) for which:

R7 is a phenyl or pyridinyl group, this group being optionallysubstituted with one or more substituents selected, independently ineach instance, from: cyano, halogen, (C₁-C₆)alkyl, OR′4, CH₂OH, CH₂NH₂,S(O)_(n)R′4, R8 and OR8;

-   -   wherein:    -   R′4 is a hydrogen atom or a (C₁-C₆)alkyl or aryl group, said        alkyl and aryl groups being optionally substituted with a        hydrogen atom or an NH₂ or OH group;    -   n is 1 or 2;    -   R8 is a halo(C₁-C₆)alkyl group.

Subgroup 54 is defined by the compounds of formula (I″) for which:

R7 is a phenyl or pyridinyl group, this group being optionallysubstituted with one or more substituents selected, independently ineach instance, from: halogen, such as fluorine, (C₁-C₆)alkyl, such asmethyl, OR′4 and OR8;

-   -   wherein:    -   R′4 is a (C₁-C₆)alkyl group, such as methyl or ethyl;    -   R8 is a halo(C₁-C₆)alkyl group, such as CF₃.

Subgroup 55 is defined by the compounds of formula (I″) for which R andR7 are defined in one of subgroups 43 to 54 above.

Subgroup 56 is defined by the compounds of formula (I″) for which:

R is a phenyl, pyridinyl or pyrazolyl group substituted with R1, R′1, R2and R3;R1 is selected from the following groups: (C₁-C₆)alkyl, such asisopropyl, (C₁-C₆)alkoxy, such as methoxy or isopropyloxy;R′1 is a hydrogen atom;R2 is selected from:

-   -   a hydrogen or chlorine atom or a methyl group;        -   a pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl,            1,7-diazaspiro[4.4]non-7-yl or pyrazolyl group;            these groups being optionally substituted with at least one            (C₁-C₆)alkyl group;            R3 is a hydrogen atom or a (C₁-C₆)alkyl group, such as a            methyl;            R7 is a phenyl or pyridinyl group, this group being            optionally substituted with one or more substituents            selected, independently in each instance, from: cyano,            halogen, (C₁-C₆)alkyl, OR′4, CH₂OH, CH₂NH₂, S(O)_(n)R′4, R8            and OR8;    -   wherein:    -   R′4 is a hydrogen atom or a (C₁-C₆)alkyl or aryl group, said        alkyl and aryl groups being optionally substituted with a        halogen atom or an NH₂ or OH group;    -   n is 1 or 2;    -   R8 is a halo(C₁-C₆)alkyl group.

Subgroup 57 is defined by the compounds of formula (I″) for which:

R is selected from the following groups:

R1 is selected from the following groups: (C₁-C₆)alkyl, such asisopropyl, and (C₁-C₆)alkoxy, such as methoxy or isopropyloxy;R′1 is a hydrogen atom:R2 is a substituent selected from a pyrrolidinyl, piperidinyl,piperazinyl, tetrahydropyranyl, 1,7-diazaspiro[4.4]non-7-yl or pyrazolylgroup;these groups being optionally substituted with at least one (C₁-C₆)alkylgroup, such as methyl;R3 is a hydrogen atom or a (C₁-C₆)alkyl group, such as a methyl;R7 is a phenyl or pyridinyl group, this group being optionallysubstituted with one or more substituents selected, independently ineach instance, from: cyano, halogen, (C₁-C₆)alkyl, OR′4, CH₂OH, CH₂NH₂,S(O)_(n)R′4, R8 and OR8;

-   -   wherein:    -   R′4 is a hydrogen atom or a (C₁-C₆)alkyl or aryl group, said        alkyl and aryl groups being optionally substituted with a        halogen atom or an NH₂ or OH group;    -   n is 1 or 2;    -   R8 is a halo(C₁-C₆)alkyl group.

Subgroup 58 is defined by the compounds of formula (I″) for which:

R is an (A) group

R1 is an isopropyloxy group;R′1 is a hydrogen atom;R2 is a piperidinyl or piperazinyl group, these groups being optionallysubstituted with at least one (C₁-C₆)alkyl group, such as methyl;R3 is a hydrogen atom or a (C₁-C₆)alkyl group, such as a methyl;R7 is a phenyl or pyridinyl group, this group being optionallysubstituted with one or more substituents selected, independently ineach instance, from:halogen, such as fluorine, (C₁-C₆)alkyl, such as methyl, OR′4 and OR8;

-   -   wherein:    -   R′4 is a (C₁-C₆)alkyl group, such as methyl or ethyl;    -   R8 is a halo(C₁-C₆)alkyl group, such as CF₃.

More particularly, the present invention relates to the followingcompounds:

-   2-({2-methoxy-4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)-7-phenylthieno-[3,2-d]pyrimidine-6-carboxamide;-   2-({2-methyl-4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)-7-phenylthieno-[3,2-d]pyrimidine-6-carboxamide;-   7-(3-chlorophenyl)-2-({2-methoxy-4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}-amino)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(4-chlorophenyl)-2-({2-methoxy-4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}-amino)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({2-methoxy-4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)-7-(thiophen-3-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({2-methoxy-4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)-7-(thiophen-2-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({2-methoxy-4-[4-(propan-2-yl)piperazin-1-yl]phenyl}amino)-7-phenylthieno-[3,2-d]pyrimidine-6-carboxamide;-   2-({2-methoxy-4-[1-(propan-2-yl)piperidin-4-yl]phenyl}amino)-7-phenylthieno-[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]-amino}thieno[3,2-d]pyrimidine-6-carboxamide:-   7-(4-fluoro-3-methoxyphenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(4-methoxyphenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]-amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(4-fluorophenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]-amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[2-methoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl]amino}-7-phenylthieno[3,2-d]pyrimidine-6-carboxamide;-   7-(4-fluoro-2-methoxyphenyl)-2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]-amino}thieno[3,2-d]pyrimidine-6-carboxamide-   2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-7-(3-methoxyphenyl)-thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]-amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[5-methyl-4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-phenylthieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[2-methoxy-5-methyl-4-(1-methylpiperidin-3-yl)phenyl]amino}-7-phenylthieno[3,2-d]pyrimidine-6-carboxamide;-   2-({2-methoxy-4-[1-(propan-2-yl)piperidin-4-yl]phenyl}amino)-7-phenylthieno-[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(1-methyl-1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-ethoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]-amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(3-methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]-amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[5-methyl-4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(pyridin-2-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(4-methyl-1,4-diazepan-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-phenylthieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-fluoro-5-methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(3-cyanophenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]-amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-phenylthieno-[3,2-d]pyrimidine-6-carboxamide;-   2-({4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(propan-2-yloxy)-phenyl}amino)-7-phenylthieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[5-methyl-4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-methoxy-2-(propan-2-yloxy)phenyl]amino}-7-phenylthieno[3,2-d]-pyrimidine-6-carboxamide;-   2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-[3-(methylsulfinyl)phenyl]thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-cyanophenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]-amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1H-imidazol-1-yl-2-(propan-2-yloxy)phenyl]amino}-7-phenylthieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-{methyl[2-(pyrrolidin-1-yl)ethyl]amino}-2-(propan-2-yloxy)phenyl]amino}-7-phenylthieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[6-(4-methylpiperazin-1-yl)-4-(propan-2-yloxy)pyridin-3-yl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[6-(1-methylpiperidin-4-yl)-4-(propan-2-yloxy)pyridin-3-yl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(5-fluoro-2-methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(3-fluoro-2-methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-[2-(methylsulfinyl)phenyl]thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({4-[3-(dimethylamino)pyrrolidin-1-yl]-2-(propan-2-yloxy)phenyl}amino)-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[4-{methyl[2-(pyrrolidin-1-yl)ethyl]amino}-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide-   7-(2-fluoro-3-methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1-ethylpiperidin-3-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-fluorophenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]-amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(1H-pyrrol-2-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-[2-fluoro-5-(hydroxymethyl)phenyl]-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide-   2-{[4-(5-methoxy-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(propan-2-yloxy)-phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(4-fluoro-2-methoxyphenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1H-imidazol-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)-thieno[3,2-d]pyrimidine-6-carboxamide;-   2-methylpropan-2-yl    4-[5-{[6-carbamoyl-7-(2-methoxyphenyl)thieno-[3,2-d]pyrimidin-2-yl]amino}-1-(propan-2-yl)-1H-pyrazol-3-yl]piperidine-1-carboxylate;-   7-(2-methoxyphenyl)-2-{[2-(propan-2-yloxy)-4-(2,2,6,6-tetramethylpiperidin-4-yl)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(2,6-dimethylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(2-ethylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[4-(piperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(4-fluoro-2-methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(3,5-dimethylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[2-(propan-2-yloxy)-4-(3,4,5-trimethylpiperazin-1-yl)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(propan-2-yloxy)-phenyl}amino)-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[3-(piperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({4-[(3R)-1-ethylpiperidin-3-yl]-2-(propan-2-yloxy)phenyl}amino)-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({4-[(3S)-1-ethylpiperidin-3-yl]-2-(propan-2-yloxy)phenyl}amino)-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(thiophen-3-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(5-fluoro-2-methoxypyridin-4-yl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-({2-(propan-2-yloxy)-4-[(2R,4S)-2-(propan-2-yl)-piperidin-4-yl]phenyl}amino)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-({2-(propan-2-yloxy)-4-[(2R,4R)-2-(propan-2-yl)-piperidin-4-yl]phenyl}amino)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-chlorophenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]-amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(propan-2-yloxy)-phenyl}amino)-7-(2-methoxypyridin-3-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(3-chlorophenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]-amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methylphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]-amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2,5-dimethoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-[2-(difluoromethoxy)phenyl]-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({4-[3-(2-hydroxyethyl)-4-methylpiperazin-1-yl]-2-(propan-2-yloxy)-phenyl}amino)-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-{[5-methyl-4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({4-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(propan-2-yloxy)phenyl}amino)-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[4-(3-methoxypyridin-4-yl)-2-(propan-2-yloxy)phenyl]-amino}thieno[3,2-d]pyrimidine-6-carboxamide:-   7-(2-methoxyphenyl)-2-{[6-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)pyridin-3-yl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({4-[(2S,4S)-2-ethyl-1-methylpiperidin-4-yl]-2-(propan-2-yloxy)phenyl}-amino)-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({4-[(2S,4R)-2-ethyl-1-methylpiperidin-4-yl]-2-(propan-2-yloxy)phenyl}-amino)-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-({2-(propan-2-yloxy)-4-[1-(propan-2-yl)piperidin-4-yl]phenyl}amino)thieno[3,2-d]pyrimidine-6-carboxamide-   7-(5-fluoro-2-methoxypyridin-3-yl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(5-fluoro-2-methoxypyridin-3-yl)-2-({2-(propan-2-yloxy)-4-[1-(propan-2-yl)-piperidin-4-yl]phenyl}amino)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(5-fluoro-2-methoxypyridin-3-yl)-2-{[5-methyl-4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(6-methoxypyridin-2-yl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-chlorophenyl)-2-({4-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(propan-2-yloxy)-phenyl}amino)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[6-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)pyridin-3-yl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({4-[3-(diethylamino)pyrrolidin-1-yl]-2-(propan-2-yloxy)phenyl}amino)-7-(2-methoxypyridin-3-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({4-[3-(dimethylamino)pyrrolidin-1-yl]-2-(propan-2-yloxy)phenyl}amino)-7-(1-methyl-1H-pyrrol-2-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(1-methyl-1H-pyrrol-2-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methylpyriidin-3-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(furan-2-yl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-[5-(aminomethyl)furan-2-yl]-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-{[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(1H-pyrrol-3-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({4-[3-(dimethylamino)pyrrolidin-1-yl]-2-(propan-2-yloxy)phenyl}amino)-7-(2-methoxypyridin-3-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-ethoxypyridin-3-yl)-2-({2-(propan-2-yloxy)-4-[1-(propan-2-yl)piperidin-4-yl]-phenyl}amino)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-ethoxypyridin-3-yl)-2-{[5-methyl-4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-ethoxypyridin-3-yl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-ethoxypyridin-3-yl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxy-5-methylpyridin-3-yl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxy-5-methylpyridin-3-yl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(5-fluoro-2-methoxypyridin-3-yl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxy-5-methylpyridin-3-yl)-2-{[5-methyl-4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(1-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({4-[3-(2-methoxyethyl)-4-methylpiperazin-1-yl]-2-(propan-2-yloxy)-phenyl}amino)-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[4-{(3R)-3-[methyl(oxetan-3-yl)amino]piperidin-1-yl}-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methylfuran-3-yl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(6-methoxypyridin-2-yl)-2-{[5-methyl-4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({4-[3-(dimethylamino)pyrrolidin-1-yl]-5-methyl-2-(propan-2-yloxy)-phenyl}amino)-7-(2-methoxypyridin-3-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({4-[3-(dimethylamino)pyrrolidin-1-yl]-5-methyl-2-(propan-2-yloxy)-phenyl}amino)-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({3-[1-(oxetan-3-yl)piperidin-4-yl]-1-(propan-2-yl)-1H-pyrazol-5-yl}amino)-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxy-6-methylpyridin-3-yl)-2-{[5-methyl-4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxy-6-methylpyridin-3-yl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxy-6-methylpyridin-3-yl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[3-(1-ethylpiperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamide;-   2-({4-[(3R,4S)-3-hydroxy-1-methylpiperidin-4-yl]-2-(propan-2-yloxy)-phenyl}amino)-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-({4-[(8S,8aS)-octahydroindolizin-8-yl]-2-(propan-2-yloxy)phenyl}amino)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-({4-[(8R,8aS)-octahydroindolizin-8-yl]-2-(propan-2-yloxy)phenyl}amino)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[4-(1-methyl-1H-pyrazol-4-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-[(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)amino]thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-{[4-(2-methyl-1H-imidazol-1-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[5-fluoro-4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[5-fluoro-4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxypyridin-3-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-{[5-methyl-4-(2-methyl-1H-imidazol-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[2-(propan-2-yloxy)-4-(1H-1,2,4-triazol-1-yl)phenyl]-amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-[(1-phenyl-1H-pyrazol-5-yl)amino]thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[4-(1-methyl-1H-pyrazol-3-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-{[3-methyl-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-fluorophenyl)-2-{[5-methyl-4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-[(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)amino]thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(4-fluoro-2-methoxyphenyl)-2-{[3-(piperidin-3-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[3-cyclopropyl-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-7-(2-methoxypyridin-3-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(4-fluoro-2-methoxyphenyl)-2-{[1-(propan-2-yl)-3-(pyridin-3-yl)-1H-pyrazol-5-yl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-[(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl)amino]thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(4-fluoro-2-methoxyphenyl)-2-{[2-(propan-2-yloxy)-4-(1H-1,2,4-triazol-1-yl)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(2,4-dimethyl-1H-imidazol-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxypyridin-3-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-methoxy-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxypyridin-3-yl)-thieno[3,2-d]pyrimidine-6-carboxamide;-   2-[(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)amino]-7-(2-methoxyphenyl)-thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-(propan-2-yloxy)-phenyl]amino}-7-(2-methoxypyridin-3-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1-cyclopropylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1-cyclopropylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(5-fluoro-2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1-cyclopropylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxypyridin-3-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-{[4-(4-methyl-1H-imidazol-1-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(4-fluoro-2-methoxyphenyl)-2-[(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl)amino]thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(1-oxidopyridin-2-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(1-ethyl-1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-ethoxypyridin-3-yl)-2-{[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(5-fluoro-2-methoxypyridin-3-yl)-2-{[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxy-6-methylpyridin-3-yl)-2-{[4-(2-methyl-1H-imidazol-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-({4-[(4-methylpiperazin-1-yl)methyl]-2-(propan-2-yloxy)phenyl}amino)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxy-6-methylpyridin-3-yl)-2-{[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[1-methyl-2-oxo-6-(propan-2-yloxy)-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-{[1-methyl-2-oxo-6-(propan-2-yloxy)-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[5-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[2-(propan-2-yloxy)-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(3-methoxypyridin-2-yl)-2-{[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(4-hydroxypiperidin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxypyridin-3-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-({4-[(1-methylpiperidin-4-yl)amino]-2-(propan-2-yloxy)phenyl}amino)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[1-cyclobutyl-3-(1-ethylpiperidin-4-yl)-1H-pyrazol-5-yl]amino}-7-(4-fluoro-2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-({4-[(4-methylpiperazin-1-yl)methyl]-2-(propan-2-yloxy)phenyl}amino)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-{[4-(1-methylpyrrolidin-3-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[3-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(5-fluoro-2-methoxypyridin-3-yl)-2-{[1-(propan-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(5-fluoro-2-methoxypyridin-3-yl)-2-{[3-methyl-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-[(5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-7-yl)amino]thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[1-(propan-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-{[3-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-{[5-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-({4-[(1-methylpiperidin-4-yl)amino]-2-(propan-2-yloxy)phenyl}amino)thieno[3,2-d]pyrimidine-6-carboxamide;-   2-{[4-(4-ethylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxypyridin-3-yl)thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[1-methyl-2-oxo-8-(propan-2-yloxy)-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxyphenyl)-2-{[1-(propan-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-{[1-methyl-2-oxo-8-(propan-2-yloxy)-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   7-(2-methoxypyridin-3-yl)-2-{[4-(1-methyl-1H-pyrazol-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide;-   [7-(2-methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   [7-(2-methoxyphenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy    phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   [7-(2-methoxy-6-methylpyridin-3-yl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   [7-(5-fluoro-2-methoxypyridin-3-yl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   [7-(2-ethoxypyridin-3-yl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   [7-(2-methoxypyridin-3-yl)-2-{[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   [7-(5-fluoro-2-methoxypyridin-3-yl)-2-{[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   [7-(2-methoxy-6-methylpyridin-3-yl)-2-{[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   [7-(2-methoxy-6-methylpyridin-3-yl)-2-{[1-(propan-2-yl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   [7-(2-ethoxypyridin-3-yl)-2-{[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   [7-(2-methoxyphenyl)-2-{[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   [7-(2-methoxy-6-methylpyridin-3-yl)-2-{[4-(1-methyl-1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   [2-{[4-chloro-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxypyridin-3-yl)thieno[3,2-d]pyrimidin-6-yl]methanol;-   (2-{[3-methyl-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidin-6-yl)methanol;-   [7-(5-fluoro-2-methoxypyridin-3-yl)-2-{[3-methyl-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   (2-{[1-(propan-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidin-6-yl)methanol;-   [7-(2-methoxyphenyl)-2-{[1-(propan-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   [7-(5-fluoro-2-methoxyphenyl)-2-{[3-methyl-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   [7-(5-fluoro-2-methoxyphenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   (2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidin-6-yl)methanol;-   [7-(2-methoxypyridin-3-yl)-2-{[4-(1-methyl-1H-pyrazol-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   [7-(2-methoxyphenyl)-2-{[4-(1-methyl-1H-pyrazol-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   [2-{[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(6-methylpyridin-3-yl)thieno[3,2-d]pyrimidin-6-yl]methanol;-   [7-(2-methoxypyridin-3-yl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   [7-(2-methoxyphenyl)-2-{[4-(1-methylpyrrolidin-3-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol;-   2-(2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-7-phenylthieno[3,2-d]pyrimidin-6-yl)propan-2-ol;-   2-[2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-6-yl]propan-2-ol;    and-   2-[7-(4-fluoro-2-methoxyphenyl)-2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]propan-2-ol;    and pharmaceutically acceptable salts thereof.

The present invention also relates to a process for preparing a compoundof formula (I) as defined above, characterized in that athienopyrimidine of formula (II):

in whichR7 is as defined in formula (I) above;n is 1 or 2; andR16 is a (C₁-C₆)alkoxy group,is reacteda) with a compound of formula (IIIb) below:

in which R is as defined in formula (I) above;b) then step a) is followed:

-   -   either by a step of treating the mixture obtained with an        aqueous ammonia solution, for example in a solvent such as        methanol, which makes it possible to obtain the compounds of        formula (I) in which R6 is —CONH₂;    -   or by a step of reducing the mixture obtained with a reducing        agent, such as DIBALH, in a solvent such as toluene or THF,        which makes it possible to obtain the compounds of formula (I)        in which R6 is a —C(R_(α))(R_(β))(OH) group where R_(α) and        R_(β) are hydrogen atoms;        -   or by a step of treating the mixture obtained with an excess            of an organometallic derivative (R_(α)MgX or R_(β)Li for            example) in a solvent such as THF, which makes it possible            to obtain the compounds of formula (I) in which R6 is a            —C(R_(α))(R_(β))(OH) group where R_(α) and R_(β) are            identical and are a (C₁-C₆)alkyl group.

According to one particular embodiment of step a), the reaction betweenthe compounds (II) and (IIIb) is carried out in the presence of anorganic or inorganic base, in a polar aprotic solvent.

The products of formula (II) can be prepared according to schemes 1 and2 hereinafter.

L1=leaving group such as OSO₂CF₃ or OTs.

The commercial 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylic acid(1) is converted into ester (2) by reaction with methanol in thepresence of acid as a catalyst. The treatment of the ester (2) withmethyl sulfanylacetate in the presence of a base such as sodium hydride,potassium carbonate, sodium carbonate or caesium carbonate in a polaraprotic solvent such as DMF or THF gives a derivative (V). Thederivative (V) can also be isolated in salt form. Finally, the hydroxylgroup can be converted into a leaving group by reaction with a sulfonicanhydride or sulfonic acid chloride, in the presence of a base such aspyridine, potassium carbonate, sodium carbonate or caesium carbonate, ina polar aprotic solvent such as DMF or THF.

A Suzuki-type metallo-catalyzed coupling reaction on the compound (VI)makes it possible to install the (hetero)aryl R7 group in position 7.This reaction can precede or follow a reaction of oxidation of thesulfur with an oxidizing agent such as 3-chloroperbenzoic acid, aqueoushydrogen peroxide, sodium perborate tetrahydrate or sodium bromate inorder to prepare the derivatives II (n=1, 2).

Alternatively, the products of formula (VII) can be prepared accordingto scheme 3, where R16 is a methoxy group.

Heating of the 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylic acid(1) in the presence of an aldehyde, in an apolar solvent such astoluene, gives a benzyl alcohol (IX) (J. Heterocyclic Chem. 2003, 40,219). Oxidation of the alcohol with manganese dioxide or a Swern-typereaction gives a ketone (X). Treatment of the ketone (X) with methylsulfanylacetate in the presence of a base such as sodium hydride,potassium carbonate, sodium carbonate or caesium carbonate, in a polaraprotic solvent such as DMF or THF, at a temperature between ambienttemperature and the reflux temperature, gives the derivative (VII).

Alternatively, the products of formula (I′) can be prepared according toscheme 4.

Treatment of the derivatives (VII) for which R16 is a methoxy group,with an aqueous ammonia solution, in a solvent such as methanol, ethanolor water, gives carboxamide derivatives (XI). The sulfur is thenoxidized with an oxidizing agent such as 3-chloroperbenzoic acid,aqueous hydrogen peroxide, sodium perborate tetrahydrate, magnesiummonoperoxyphthalate or sodium bromate, in order to prepare thederivatives (XII) with n=1 or 2. Finally, the reaction of a compound offormula (IIIb) with the thienopyrimidine (XII) in the presence of anorganic base such as DBU or BTTP, or an inorganic base such as sodiumhydride, caesium carbonate or potassium carbonate, in a polar aproticsolvent such as DMF, DMA, DMSO or THF, gives the compounds (I′).

Alternatively, the products of formula (I″) can be prepared according toscheme 5.

Reaction of the derivatives (VIIa) for which R16 is a methoxy group,with a reducing agent such as DIBALH, in a solvent such as THF ortoluene, gives alcohol derivatives (XIII), for which the R_(α) and R_(β)groups are hydrogen atoms.

Reaction of the derivatives (VIIa) for which R16 is a methoxy group,with an excess of an organometallic derivative (R_(α)MgX or R_(α)Li, forexample) in a solvent such as THF, gives alcohol derivatives (XIII) forwhich the R_(α) and R_(β) groups are identical and are a (C₁-C₆)alkylgroup.

Alcohol derivatives (XIII) for which the R_(α) and R_(β) groups arealkyl groups that are different from one another can be obtained bymeans of a Weinreb amide (VIIb) for which R16 is N(OCH₃)CH₃ (obtainedafter hydrolysis of the ester (VIIa) with NaOH or LiOH and formation ofthe Weinreb amide according to the methods known to those skilled in theart), by addition of an organometallic derivative R_(α)MgX or R_(α)Li,and then by treatment of the resulting ketone with another derivativeR_(β)MgX or R_(β)Li.

Alcohol derivatives (XIII) for which one of the R_(α) or R_(β) groups isa hydrogen and the other an alkyl group can be obtained by means of aWeinreb amide (VIIb) for which R16 is N(OCH₃)CH₃, by addition of anorganometallic derivative RMgX or RLi, and then by treatment of theresulting ketone with a reducing agent such as sodium borohydride inmethanol or DIBALH, in a solvent such as THF or toluene.

Alcohol derivatives (XIII) for which the R_(α) and R_(β) groups togetherform, with the carbon atom which bears them, a 3-membered carbocycle canbe obtained by reaction with ethylmagnesium bromide in the presence oftitanium IV isopropoxide, in a solvent such as THF or ether (see, forexample, Tetrahedron 2011, 67(33), 5979).

Alcohol derivatives (XIII) for which the R_(α) and R_(β) groups togetherform, with the carbon atom which bears them, a 4- to 5-memberedcarbocycle can be obtained by reaction with the bismagnesium reagentsderived from 1,3-dibromopropane or 1,4-dibromobutane in a solvent suchas THF (see, for example, European Journal of Organic Chemistry 2004,24, 4995).

The sulfur of the compounds (XIII) is then oxidized with an oxidizingagent such as 3-chloroperbenzoic acid, aqueous hydrogen peroxide,magnesium monoperoxyphthalate, sodium perborate tetrahydrate or sodiumbromate, in order to prepare the derivatives (XIV) with n=1 or 2.Finally, the reaction of a compound of formula (IIIb) with thethienopyrimidine (XIV) in the presence of an organic base such as DBU orBTTP, or an inorganic base such as sodium hydride, caesium carbonate orpotassium carbonate, in a polar aprotic solvent such as DMF, DMA, DMSOor THF, gives the compounds (I″).

The preparation of the compounds of formula (IIIb) can be carried outaccording to scheme 6.

The products of formula (IIIb) can be prepared from the compounds (IIIa)by reaction with formic acid, optionally in the presence of aceticanhydride, at a temperature between ambient temperature and the refluxtemperature. Most of the compounds (IIIa) are prepared according to themethods known to those skilled in the art.

The present invention also relates to the compounds of general formulae(II), (XII) and (XIV), as well as pharmaceutically acceptable saltsthereof. These compounds are of use as synthesis intermediates for thepreparation of the compounds of general formula (I).

Tables A and B hereinafter describe compounds of the invention, without,however, being limiting.

TABLE A Compounds of formula (I') (I')

R7 R R1 R2 R3 R'1 1

(A) OCH₃

H H 2

(A) CH₃

H H 3

(A) OCH₃

H H 4

(A) OCH₃

H H 5

(A) OCH₃

H H 6

(A) OCH₃

H H 7

(A) OCH₃

H H 8

(A) OCH₃

H H 9

(A) isopropyloxy

H H 10

(A) isopropyloxy

H H 11

(A) isopropyloxy

H H 12

(A) isopropyloxy

H H 13

(A) OCH₃

Me H 14

(A) isopropyloxy

H H 15

(A) OCH₃

H H 16

(A) isopropyloxy

H H 17

(A) isopropyloxy

Me H 18

(A) OCH₃

Me H 19

(A) isopropyloxy

H H 20

(A) isopropyloxy

H H 21

(A) isopropyloxy

H H 22

(A) isopropyloxy

Me H 23

(A) isopropyloxy

H H 24

(A) isopropyloxy

H H 25

(A) isopropyloxy

H H 26

(A) isopropyloxy

H H 27

(A) isopropyloxy

H H 28

(A) isopropyloxy

H H 29

(A) isopropyloxy

H H 30

(A) isopropyloxy

Me H 31

(A) isopropyloxy OMe H H 32

(A) isopropyloxy

H H 33

(A) isopropyloxy

H H 34

(A) isopropyloxy

H H 35

(A) isopropyloxy

H H 36

(A) isopropyloxy

H H 37

(B) isopropyloxy

— H 38

(B) isopropyloxy

— H 39

(A) isopropyloxy

H H 40

(A) isopropyloxy

H H 41

(A) isopropyloxy

H H 42

(A) isopropyloxy

H H 43

(A) isopropyloxy

H H 44

(A) isopropyloxy

H H 45

(A) isopropyloxy

H H 46

(A) isopropyloxy

H H 47

(A) isopropyloxy

H H 48

(A) isopropyloxy

H H 49

(A) isopropyloxy

H H 50

(A) isopropyloxy

H H 51

(A) isopropyloxy

H H 52

(D) isopropyloxy

— H 53

(A) isopropyloxy

H H 54

(A) isopropyloxy

H H 55

(A) isopropyloxy

H H 56

(A) isopropyloxy

H H 57

(A) isopropyloxy

H H 58

(A) isopropyloxy

H H 59

(A) isopropyloxy

H H 60

(A) isopropyloxy

H H 61

(D) isopropyloxy

— H 62

(A) isopropyloxy

H H 63

(A) isopropyloxy

H H 64

(A) isopropyloxy

H H 65

(A) isopropyloxy

H H 66

(A) isopropyloxy

H H 67

(A) isopropyloxy

H H 68

(A) isopropyloxy

H H 69

(A) isopropyloxy

H H 70

(D) isopropyloxy

— H 71

(A) isopropyloxy

H H 72

(A) isopropyloxy

H H 73

(A) isopropyloxy

H H 74

(A) isopropyloxy

H H 75

(A) isopropyloxy

H H 76

(A) isopropyloxy

H H 77

(A) isopropyloxy

H H 78

(A) isopropyloxy

Me H 79

(A) isopropyloxy

H H 80

(A) isopropyloxy

H H 81

(A) isopropyloxy

H H 82

(C) isopropyloxy

H H 83

(A) isopropyloxy

H H 84

(A) isopropyloxy

H H 85

(A) isopropyloxy

H H 86

(A) isopropyloxy

H H 87

(A) isopropyloxy

H H 88

(A) isopropyloxy

H H 89

(A) isopropyloxy

CH₃ H 90

(A) isopropyloxy

H H 91

(A) isopropyloxy

H H 92

(C) isopropyloxy

H H 93

(A) isopropyloxy

H H 94

(A) isopropyloxy

H H 95

(A) isopropyloxy

H H 96

(A) isopropyloxy

H H 97

(A) isopropyloxy

H H 98

(A) isopropyloxy

H H 99

(A) isopropyloxy

H H 100

(A) isopropyloxy

CH₃ H 101

(A) isopropyloxy

H H 102

(A) isopropyloxy

H H 103

(A) isopropyloxy

H H 104

(A) isopropyloxy

CH₃ H 105

(A) isopropyloxy

CH₃ H 106

(A) isopropyloxy

H H 107

(A) isopropyloxy

H H 108

(A) isopropyloxy

H H 109

(A) isopropyloxy

H H 110

(A) isopropyloxy

H H 111

(A) isopropyloxy

CH₃ H 112

(A) isopropyloxy

H H 113

(A) isopropyloxy

H H 114

(A) isopropyloxy

H H 115

(A) isopropyloxy

H H 116

(A) isopropyloxy

CH₃ H 117

(A) isopropyloxy

CH₃ H 118

(A) isopropyloxy

CH₃ H 119

(D) isopropyl

— H 120

(A) isopropyloxy

CH₃ H 121

(A) isopropyloxy

H H 122

(A) isopropyloxy

H H 123

(D) isopropyl

— H 124

(A) isopropyloxy

H H 125

(A) isopropyloxy

H H 126

(A) isopropyloxy

H H 127

(A) isopropyloxy

H H 128

(A) H

fused with phenyl H 129

(A) isopropyloxy

H H 130

(A) isopropyloxy

F H 131

(A) isopropyloxy

F H 132

(A) isopropyloxy

CH₃ H 133

(A) isopropyloxy

H H 134

(D)

H — H 135

(A) isopropyloxy

H H 136

(D) isopropyl methyl — H 137

(A) isopropyloxy

CH₃ H 138

(A) H

fused with phenyl H 139

(D) isopropyl

— H 140

(D) isopropyl cyclopropyl — H 141

(D) isopropyl

— H 142

(A) H

fused with phenyl H 143

(A) isopropyloxy

H H 144

(A) isopropyloxy

H H 145

(A) isopropyloxy methoxy H H 146

(D)

cyclopropyl — H 147

(A) isopropyloxy

H H 148

(A) isopropyloxy

H H 149

(A) isopropyloxy

H H 150

(A) isopropyloxy

H H 151

(A) isopropyloxy

H H 152

(A) H

fused with phenyl H 153

(A) isopropyloxy

H H 154

(A) isopropyloxy

H H 155

(A) isopropyloxy

CH₃ H 156

(A) isopropyloxy

H H 157

(A) isopropyloxy

CH₃ H 158

(A) isopropyloxy

H H 159

(A) isopropyloxy

H H 160

(A) isopropyloxy

CH₃ H 161

(A) H

fused with phenyl isopropyloxy 162

(A) H

fused with phenyl isopropyloxy 163

(A) isopropyloxy

H H 164

(A) isopropyloxy

H H 165

(A) isopropyloxy

CH₃ H 166

(A) isopropyloxy

H H 167

(A) isopropyloxy

H H 168

(D) cyclobutyl

— H 169

(A) isopropyloxy

H H 170

(A) isopropyloxy

H H 171

(E) isopropyloxy

— H 172

(D) isopropyl

— H 173

(D) isopropyl CH₃ — H 174

(A) H

fused with phenyl H 175

(D) isopropyl

— H 176

(E) isopropyloxy

— H 177

(F) isopropyloxy

— H 178

(A) isopropyloxy

— H 179

(A) isopropyloxy

H H 180

(A) isopropyloxy

fused with phenyl H 181

(D) isopropyl

— H 182

(A) isopropyloxy

fused with phenyl H 183

(A) isopropyloxy

H H

TABLE B Compounds of formula (I″) (I″)

R7 R R1 R2 R3 Rα Rβ R′1 184

(A) isopropyloxy

H H H H 185

(A) isopropyloxy

H H H H 186

(A) isopropyloxy

H H H H 187

(A) isopropyloxy

H H H H 188

(A) isopropyloxy

H H H H 189

(A) isopropyloxy

CH₃ H H H 190

(A) isopropyloxy

CH₃ H H H 191

(A) isopropyloxy

CH₃ H H H 192

(D) isopropyl

— H H H 193

(A) isopropyloxy

CH₃ H H H 194

(A) isopropyloxy

CH₃ H H H 195

(A) isopropyloxy

H H H H 196

(A) isopropyloxy Cl H H H H 197

(D) isopropyl CH₃ — H H H 198

(D) isopropyl CH₃ — H H H 199

(D) isopropyl

— H H H 200

(D) isopropyl

— H H H 201

(D) isopropyl CH₃ — H H H 202

(A) isopropyloxy

H H H H 203

(A) isopropyloxy

H H H H 204

(A) isopropyloxy

H H H H 205

(A) isopropyloxy

H H H H 206

(A) sopropyloxy

CH₃ H H H 207

(A) isopropyloxy

H H H H 208

(A) isopropyloxy

H H H H 209

(A) OCH₃

H CH₃ CH₃ H 210

(A) OCH₃

H CH₃ CH₃ H 211

(A) OCH₃

H CH₃ CH₃ H

The following examples describe the preparation of certain compounds inaccordance with the invention. These examples are not limiting andmerely illustrate the present invention. The numbers of the compoundsexemplified refer back to those given in the table hereinafter, whichillustrates the chemical structures and the physical properties of somecompounds according to the invention.

EXAMPLES I—Materials and Methods

The ¹H NMR spectra at 250, 400 and 500 MHz were performed on a BrukerAvance 250, Bruker Avance DRX-400 or Bruker Avance DPX-500 spectrometerwith the chemical shifts (δ in ppm) in dimethyl sulfoxide-d6 (DMSO-d6)referenced at 2.5 ppm at the temperature of 303K.

The mass spectra (SM) were obtained by methods A to E.

Method A:

Waters UPLC-SQD apparatus; ionization: electrospray in positive and/ornegative mode (ES+/−); chromatographic conditions: column: Acquity BEHC18 1.7 μm-2.1×50 mm; solvents: A: H₂O (0.1% formic acid) B: CH₃CN (0.1%formic acid); column temperature: 50° C.; flow rate: 1 ml/min; gradient(2 min): from 5 to 50% of B in 0.8 min; 1.2 min: 100% of B; 1.85 min:100% of B; 1.95: 5% of B; retention time=Tr (min).

Method B:

Waters UPLC-SQD apparatus; ionization: electrospray in positive and/ornegative mode (ES+/−); chromatographic conditions: column: Acquity BEHC18 1.7 μm-2.1×50 mm; solvents: A: H₂O (0.1% formic acid) B: CH₃CN (0.1%formic acid); column temperature: 50° C.; flow rate: 0.8 ml/min;gradient (2.5 min): from 5 to 100% of B in 1.8 min; 2.4 min: 100% of B;2.45 min: 100% to 5% of B in 0.05 min; retention time=Tr (min).

Method C:

Waters UPLC-XEVO/QTof apparatus; ionization: electrospray in positivemode; chromatographic conditions: column: Acquity UPLC BEH C8 1.7μm-2.1×100 mm; solvents: A: H₂O (0.1% formic acid) B: CH₃CN (0.1% formicacid); column temperature: 55° C.; flow rate: 0.55 ml/min; gradient (11min): from 5 to 97% of B in 8.3 min; 8.6 min: 100% of B; 9 min: 5% of B;retention time=Tr (min).

Method D

Waters ZQ apparatus; ionization: electrospray in positive and/ornegative mode (ES+/−); chromatographic conditions: column: XBridge C182.5 μm-3×50 mm; solvents: A: H₂O (0.1% formic acid) B: CH₃CN (0.1%formic acid); column temperature: 70° C.; flow rate: 0.9 ml/min:gradient (7 min): from 5 to 100% of B in 5.3 min; 5.5 min: 100% of B:6.3 min: 5% of B; retention time=Tr (min).

Method E:

Waters UPLC-TOF apparatus; ionization: electrospray in positive mode;chromatographic conditions: column: Acquity UPLC BEH C8 1.7 μm-2.1×50mm; solvents: A: H₂O (0.05% TFA) B: CH₃CN (0.035% TFA); columntemperature: 40° C.; flow rate: 1.0 ml/min; gradient (3 min): T0: 98% ofA; T1.6 min to T2.1 min: 100% B; T2.5 min to T3 min: 98% A.

The microwave oven used is a Biotage, Initiator™ Eight, 400 W max, 2450MHz device or a CEM discover, 300 W max, device.

The H-cube used is a Thales-nanotechnology device.

II—Preparation of Compounds of Formulae (II) and (XII) Example 1: Methyl2-(methylsulfanyl)-7-{[(trifluoromethyl)sulfonyl]oxy}thieno[3,2-d]pyrimidine-6-carboxylate

16.0 g of chloro(trimethyl)silane are added dropwise to a solution of6.2 g of 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylic acid 1 in100 ml of methanol and 100 ml of dichloromethane. The mixture is stirredat ambient temperature for 20 h, and then concentrated under vacuum. Theresidue is taken up with water and extracted with dichloromethane. Theorganic phase is dried over magnesium sulfate and concentrated undervacuum so as to obtain 6.3 g of methyl5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylate 2 in the form of abrown oil.

1.2 g of sodium hydride (60% in oil) are added slowly to a mixture of6.0 g of methyl 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylate 2and 3.0 g of methyl sulfanylacetate in 60 ml of DMF. After 15 min atambient temperature, the mixture is heated at 60° C. for 3 h, and thencooled to ambient temperature overnight. The resulting suspension isfiltered and the solid is washed with ethyl acetate and dried undervacuum so as to obtain 3.6 g of sodium6-(methoxycarbonyl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidin-7-olate 3in the form of a beige solid.

30 g of N-phenylbistrifluoromethanesulfonimide are added to a solutionof 10.0 g of sodium6-(methoxycarbonyl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidin-7-olate 3in 400 ml of anhydrous pyridine. The mixture is stirred at ambienttemperature for 48 h. and then concentrated under reduced pressure. Thereaction crude is solubilized in 400 ml of dichloromethane and then theorganic phase is washed three times with 250 ml of water. The organicphase is dried over magnesium sulfate, filtered, and then concentratedunder reduced pressure. The residue is purified on silica, elution beingcarried out with 15-30% of ethyl acetate in heptanes, so as to obtain11.6 g of methyl2-(methylsulfanyl)-7-{[(trifluoromethyl)sulfonyl]oxy}thieno[3,2-d]pyrimidine-6-carboxylate4 in the form of a whitish powder. Rf=0.39 (heptane/ethyl acetate:70/30).

Example 2: Methyl2-(methylsulfonyl)-7-{[(trifluoromethyl)sulfonyl]oxy}thieno[3,2-d]pyrimidine-6-carboxylate

14.3 g of 3-chloroperbenzoic acid is added slowly, in fractions, to asolution of 10.0 g of methyl2-(methylsulfanyl)-7-{[(trifluoromethyl)sulfonyl]oxy}thieno[3,2-d]pyrimidine-6-carboxylate4 (example 1) in 140 ml of dichloromethane, cooled in an ice bath. Themixture is stirred for 6 h while cold, and then left at ambienttemperature overnight. The mixture is then diluted with 400 ml ofdichloromethane and treated with 300 ml of saturated sodium thiosulfatesolution. After stirring and settling out, the aqueous phase isextracted with 2×100 ml of dichloromethane. The organic phases arewashed with 400 ml of a saturated sodium bicarbonate solution, and thenwith 100 ml of a saturated sodium chloride solution. The organic phasesare dried over magnesium sulfate, filtered, and then concentrated undervacuum so as to obtain 10.8 g of methyl2-(methylsulfonyl)-7-{[(trifluoromethyl)sulfonyl]oxy}thieno[3,2-d]pyrimidine-6-carboxylate5 in the form of a white powder. ¹H NMR (DMSO-d6) δ 3.48 (s, 3H); 4.02(s, 3H); 10.01 (s, 1H).

Example 3: Methyl2-(methylsulfonyl)-7-phenylthieno[3,2-d]pyrimidine-6-carboxylate

A mixture of 253 mg of methyl2-(methylsulfonyl)-7-{[(trifluoromethyl)sulfonyl]oxy}thieno[3,2-d]pyrimidine-6-carboxylate5 (example 2), 110 mg of benzeneboronic acid, 392 mg of caesiumcarbonate and 49 mg ofdichloropalladium(II)bis(diphenylphosphino)ferocene in 3.5 ml of tolueneis heated at 90° C. for 30 min. The mixture is cooled and poured intowater. The aqueous phase is extracted three times with dichloromethane.The organic phases are dried over magnesium sulfate, filtered, and thenconcentrated under vacuum. The residue is purified on 25 g of silica,elution being carried out with dichloromethane, so as to obtain 145 mgof methyl2-(methylsulfonyl)-7-phenylthieno[3,2-d]pyrimidine-6-carboxylate in theform of a beige solid.

Example 4: Methyl2-(methylsulfanyl)-7-phenylthieno[3,2-d]pyrimidine-6-carboxylate

Anhydrous dioxane is added, under argon, to a mixture of 2.5 g of methyl2-(methylsulfanyl)-7-{[(trifluoromethyl)sulfonyl]oxy}thieno[3,2-d]pyrimidine-6-carboxylate4 (example 1) and 0.785 g of phenylboronic acid. After the addition of250 mg of dichloropalladium (dppf) and 4.09 g of BTPP, the mixture isrefluxed for 20 h, and then cooled to ambient temperature. The mixtureis filtered on silica gel, elution being carried out with ethyl acetate.The solvent is evaporated off under vacuum and the residue is trituratedwith an ethyl acetate/heptane mixture so as to obtain 1.6 g of methyl2-(methylsulfanyl)-7-phenylthieno[3,2-d]pyrimidine-6-carboxylate in theform of a whitish precipitate.

Example 5: Methyl7-[2-(difluoromethoxy)phenyl]-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxylate

A mixture of 780 mg of 2-(difluoromethoxy)benzaldehyde and 300 mg of5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylic acid 1 in 15 ml ofanisole is microwave-heated at 130° C. for 45 min and then again for 15min and again at 140° C. for 15 min. 160 mg of5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylic acid 1 is then addedand the mixture is again heated at 130° C. for 30 min. The mixture isconcentrated under vacuum and purified on 40 g of silica, elution beingcarried out with 0-10% of ethyl acetate in heptane, so as to obtain 268mg of[5-chloro-2-(methylsulfanyl)pyrimidin-4-yl][2-(difluoromethoxy)phenyl]methanol6 in the form of a colourless oil.

A solution of 78 mg of DMSO in 0.5 ml of dichloromethane is addedslowly, under argon, to a solution of 75 mg of oxalyl chloride in 2 mlof dichloromethane, cooled to −78° C. After 20 min at −78° C. a solutionof 308 mg of[5-chloro-2-(methylsulfanyl)pyrimidin-4-yl][2-(difluoromethoxy)phenyl]methanol6 in 2 ml of dichloromethane is added. After 1 h 30 at −78° C., 182 mgof triethylamine are slowly added and the mixture is left to return toambient temperature for 30 min. The mixture is then poured into waterand extracted three times with dichloromethane. The organic phases aredried over magnesium sulfate, filtered, and then concentrated undervacuum so as to obtain 303 mg of[5-chloro-2-(methylsulfanyl)pyrimidin-4-yl][2-(difluoromethoxy)phenyl]methanone7 in the form of a pale yellow oil.

A mixture of 303 mg of[5-chloro-2-(methylsulfanyl)pyrimidin-4-yl][2-(difluoromethoxy)phenyl]methanone7, 107 mg of methyl sulfanylacetate, 253 mg of potassium carbonate and 5ml of acetonitrile is microwave-heated in a sealed tube at 60° C. for 4h. The mixture is diluted with a 0.5 N aqueous hydrochloric acidsolution and extracted twice with ethyl acetate and once withdichloromethane. The organic phases are dried over magnesium sulfate,filtered, and then concentrated under vacuum so as to obtain 343 mg ofmethyl7-[2-(difluoromethoxy)phenyl]-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxylate8 in the form of a pale yellow solid.

Example 6: Thiomethyl Oxidation

Example 6.1 Methyl2-(methylsulfonyl)-7-phenylthieno[3,2-d]pyrimidine-6-carboxylate

2.3 g of 3-chloroperoxybenzoic acid (75%) are added slowly, infractions, to a solution of 1.6 g of methyl2-(methylsulfanyl)-7-phenylthieno[3,2-d]pyrimidine-6-carboxylate(example 4) in 25 ml of dichloromethane, cooled in an ice bath. Themixture is stirred for 2.5 h while cold, and then left at ambienttemperature overnight. The mixture is then diluted with 80 ml ofdichloromethane and treated with 60 ml of saturated sodium thiosulfatesolution. After stirring and settling out, the aqueous phase isextracted with 60 ml of dichloromethane. The organic phases are washedwith 60 ml of a saturated sodium bicarbonate solution, and then with 60ml of a saturated sodium chloride solution. The organic phases are driedover magnesium sulfate, filtered, and then concentrated under vacuum soas to obtain the crude product, which is purified on 200 g of silica,elution being carried out with dichloromethane, so as to obtain 1.4 g ofmethyl 2-(methylsulfonyl)-7-phenylthieno[3,2-d]pyrimidine-6-carboxylatein the form of a white solid.

Example 6.2 Methyl7-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfinyl)thieno[3,2-d]pyrimidine-6-carboxylate

230 mg of methyl7-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxylate,prepared by analogy with the method described in example 4, are added toa mixture of 25 equivalents of hydrogen peroxide (30% in water) and 1.49g of phenol. The reaction medium is stirred for 30 minutes at ambienttemperature and then heated at 50° C. for 1 hour. The reaction medium isdiluted in ethyl acetate and washed with a saturated aqueous NaHCO₃solution and then with a saturated sodium chloride solution. The organicphase is dried over magnesium sulfate, filtered, and then concentratedunder vacuum so as to obtain the crude product, which is purified onsilica, elution being carried out with a 0-10% gradient of methanol indichloromethane so as to obtain 170 mg of methyl7-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfinyl)thieno[3,2-d]pyrimidine-6-carboxylatein the form of a beige solid.

Example 6.3 Methyl7-(2-ethoxyphenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylate

A mixture of 330 mg of methyl7-(2-ethoxyphenyl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxylate,prepared by analogy to the method described in example 4, and 634 mg ofsodium perborate tetrahydrate in 15 ml of acetic acid ismicrowave-heated at 70° C. in a sealed tube for 1 h 30. The mixture isdiluted with 5 volumes of water and the resulting precipitate isfiltered off and washed with water. The solid is taken up withdichloromethane and 100 ml of a solution of sodium thiosulfate. The pHis adjusted to pH 8-9 by adding solid potassium carbonate and theaqueous phase is extracted with dichloromethane. The organic phases aredried over magnesium sulfate, filtered, and then concentrated undervacuum. This crude is purified on 40 g of silica, elution being carriedout with dichloromethane, so as to obtain 296 mg of methyl7-(2-ethoxyphenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylatein the form of a yellow solid.

Example 6.4 Methyl7-(6-methoxypyridin-2-yl)-2-(methylsulfinyl)thieno[3,2-d]pyrimidine-6-carboxylate

24 mg of sodium bromide and 18 mg of sodium bromate are added, withstirring, to a suspension of 55 mg of methyl7-(6-methoxypyridin-2-yl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxylate,prepared by analogy to the method described in example 5, (at 50%) in 2ml of water, and then 6.5 μl of concentrated sulfuric acid are slowlyadded. The yellow suspension rapidly turns orange. After 2 h 30 minutesof stirring at ambient temperature, the yellow suspension is filteredthrough a number 4 sintered glass filter. The yellow solid is driedunder vacuum so as to obtain 28 mg of methyl7-(6-methoxypyridin-2-yl)-2-(methylsulfinyl)thieno[3,2-d]pyrimidine-6-carboxylate.

Example 7:7-(4-Fluorophenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxamide

A mixture of 200 mg of methyl2-(methylsulfanyl)-7-{[(trifluoromethyl)sulfonyl]oxy}thieno[3,2-d]pyrimidine-6-carboxylate4 (example 1), 216 mg of 4-fluorophenylboronic acid, 19 mg ofdichloropalladium (dppf) and 322 mg of BTPP in 2.5 ml of dioxane underargon is microwave-heated at 120° C. in a sealed tube for 1 h. Themedium is taken up with dichloromethane and filtered. The organic phaseis washed three times with water, then dried over magnesium sulfate,filtered, and then concentrated under vacuum so as to give a yellowsolid. The crude is purified on 80 g of silica, elution being carriedout with 0-20% of methanol in dichloromethane, so as to obtain 135 mg ofmethyl7-(4-fluorophenyl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxylatein the form of a yellow solid.

A solution of 200 mg of methyl7-(4-fluorophenyl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxylatein 75 ml of 7N ammoniacal methanol is stirred at ambient temperature for64 h. The mixture is concentrated under vacuum so as to give 135 mg of7-(4-fluorophenyl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxamidein the form of a yellow solid.

A mixture of 135 mg of7-(4-fluorophenyl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxamideand 293 mg of sodium perborate tetrahydrate in 5 ml of acetic acid ismicrowave-heated at 70° C. in a sealed tube for 1 h 30. The mixture istaken up with dichloromethane and 100 ml of a sodium thiosulfatesolution. The pH is adjusted to pH 8-9 by adding solid potassiumcarbonate and the aqueous phase is extracted with dichloromethane. Theorganic phases are dried over magnesium sulfate, filtered, and thenconcentrated under vacuum so as to obtain a beige solid. This crude ispurified on 40 g of silica, elution being carried out withdichloromethane, so as to obtain 90 mg of7-(4-fluorophenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxamidein the form of a white solid.

The compounds (II) and (XII) obtained according to examples 3 to 7 aredescribed in table 1 hereinafter.

TABLE 1 Prepared MS: Compounds according to conditions/ II/XII Nameexample No. NMR MH+/Tr II-1 Methyl 2-(methylsulfonyl)-7- 4/6.1 3.45 (s,3 H); 3.89 (s, 3 H); 7.54 A phenylthieno[3,2-d]pyrimidine- to 7.67 (m, 5H); 10.00 (s, 1 H) 349 6-carboxylate 0.82 II-2 Methyl7-(2-chlorophenyl)-2- 4/6.1 3.37 (s, 3 H); 3.81 (s, 3 H); 7.46 A(methylsulfonyl)thieno[3,2- to 7.59 (m, 3 H); 7.64 (broad d, J = 8.0 Hz,383 d]pyrimidine-6-carboxylate 1 H); 9.98 (s, 1 H) 0.87 II-3 Methyl7-(3-chlorophenyl)-2- 3 3.40 (s, 3 H); 3.85 (s, 3 H); 7.52 A(methylsulfonyl)thieno[3,2- to 7.60 (m, 3 H); 7.70 (broad s, 1 383d]pyrimidine-6-carboxylate H); 9.97 (s, 1 H) 0.93 II-4 Methyl7-(4-chlorophenyl)-2- 4/6.3 3.40 (s, 3 H); 3.85 (s, 3 H); B(methylsulfonyl)thieno[3,2- 7.57 (d, J = 8 Hz, 2 H); 7.63 (d, J = 8 Hz,383 d]pyrimidine-6-carboxylate 2 H); 9.97 (s, 1 H) 1.22 II-5 Methyl7-(2-methoxyphenyl)-2- 3 3.37 (s, 3 H); 3.68 (s, 3 H); A(methylsulfonyl)thieno[3,2- 3.80 (s, 3 H); 7.10 (broad t, J = 7.6 Hz,379 d]pyrimidine-6-carboxylate 1 H); 7.17 (dd, J = 2.0 and 7.6 Hz, 0.811 H); 7.44 (dd, J = 2.0 and 7.6 Hz, 1 H); 7.48 (m, 1 H); 9.92 (s, 1 H)II-6 Methyl 7-(3-methoxyphenyl)-2- 4/6.1 3.40 (s, 3 H); 3.80 (s, 3 H); A(methylsulfonyl)thieno[3,2- 3.84 (s, 3 H); 7.07 (ddd, J = 1.0 and 379d]pyrimidine-6-carboxylate 2.7 and 8.3 Hz, 1 H); 7.13 (dt, J = 1.3 0.83and 7.6 Hz, 1 H); 7.18 (dd, J = 1.7 and 2.4 Hz, 1 H); 7.42 (t, J = 7.9Hz, 1 H); 9.94 (s, 1 H) XII-7 7-(4-Methoxyphenyl)-2- 7 3.42 (s, 3 H);3.84 (s, 3 H); A (methylsulfonyl)thieno[3,2- 7.11 (broad d, J = 8.8 Hz,2 H); [M − H]− 362 d]pyrimidine-6-carboxamide 7.60 (broad d, J = 8.8 Hz,2 H); 0.57 7.69 (broad s, 1 H); 8.05 (broad s, 1 H); 9.86 (s, 1 H) II-8Methyl 7-(2,5- 3 3.39 (s, 3 H); 3.62 (s, 3 H); A dimethoxyphenyl)-2-3.75 (s, 3 H); 3.81 (s, 3 H); 7.00 to 409 (methylsulfonyl)thieno[3,2-7.11 (m, 3 H); 9.91 (s, 1 H) 0.82 d]pyrimidine-6-carboxylate II-9 Methyl7-(3-fluoro-2- 3 3.39 (s, 3 H); 3.67 (d, J = 2.2 Hz, A methoxyphenyl)-2-3 H); 3.82 (s, 3 H); 7.17 to 397 (methylsulfonyl)thieno[3,2- 7.27 (m, 2H); 7.39 to 7.48 (m, 1 H); 0.86 d]pyrimidine-6-carboxylate 9.96 (s, 1 H)II-10 Methyl 7-(4-fluoro-2- 3 3.38 (s, 3 H); 3.7 (s, 3 H); 3.8 (s, Amethoxyphenyl)-2- 3 H); 6.9 (m, 1 H), 7.1 (dd, J = 11.6 397(methylsulfonyl)thieno[3,2- and 2.3 Hz, 1 H), 7.48 (dd, J = 8.2 1.13d]pyrimidine-6-carboxylate and 6.6 Hz, 1 H), 9.9 (s, 1 H) II-11 Methyl7-(5-fluoro-2- 3 3.38 (s, 3 H); 3.67 (s, 3 H); A methoxyphenyl)-2- 3.82(s, 3 H); 7.19 (m, 1 H); 7.28 to 397 (methylsulfonyl)thieno[3,2- 7.37(m, 2 H); 9.93 (s, 1 H) 0.84 d]pyrimidine-6-carboxylate XII-127-(4-Fluoro-3-methoxyphenyl)- 7 3.43 (s, 3 H); 3.87 (s, 3 H); A2-(methylsulfonyl)thieno[3,2- 7.21 (ddd, J = 2.1 and 4.4 and 8.4 Hz, [M− H]− 380 d]pyrimidine-6-carboxamide 1 H); 7.39 (dd, J = 8.4 and 11.5Hz, 0.60 1 H); 7.52 (dd, J = 2.1 and 8.4 Hz, 1 H); 7.83 (broad s, 1 H);8.10 (broad s, 1 H); 9.88 (s, 1 H) II-13 Methyl 7-(2-fluoro-5- 4/6.33.40 (s, 3 H); 3.78 (s, 3 H); A methoxyphenyl)-2- 3.86 (s, 3 H); 7.11(m, 1 H); 7.19 (dd, J = 3.2 397 (methylsulfonyl)thieno[3,2- and 5.9 Hz,1 H); 7.30 (t, J = 9.3 Hz, 0.85 d]pyrimidine-6-carboxylate 1 H); 9.97(s, 1 H) II-14 Methyl 7-(2-fluoro-3- 3 3.38 (s, 3 H); 3.85 (s, 3 H); Amethoxyphenyl)-2- 3.91 (s, 3 H); 7.10 (m, 1 H); 7.21 to 397(methylsulfonyl)thieno[3,2- 7.40 (m, 2 H); 9.97 (s, 1 H) 0.82d]pyrimidine-6-carboxylate II-15 Methyl 7-(2-ethoxyphenyl)-2- 4/6.3 1.08(t, J = 6.8 Hz, 3 H); 3.38 (s, 3 A (methylsulfonyl)thieno[3,2- H); 3.80(s, 3 H); 3.98 (q, J = 6.8 Hz, 393 d]pyrimidine-6-carboxylate 2 H); 7.09(t, J = 7.5 Hz, 1 H); 0.90 7.14 (d, J = 8.0 Hz, 1 H); 7.42 to 7.50 (m, 2H); 9.92 (s, 1 H) II-16 Methyl 7-(2-fluorophenyl)-2- 3 3.38 (s, 3 H);3.85 (s, 3 H); 7.34 A (methylsulfonyl)thieno[3,2- to 7.41 (m, 2 H); 7.53to 7.64 (m, 367 d]pyrimidine-6-carboxylate 2 H); 9.97 (s, 1 H) 0.83XII-17 7-(4-Fluorophenyl)-2- 7 3.42 (s, 3 H); 7.39 (broad t, J = 8.3 Hz,A (methylsulfonyl)thieno[3,2- 2 H); 7.70 (broad dd, J = 5.5 352d]pyrimidine-6-carboxamide and 8.3 Hz, 2 H); 7.87 (broad 0.57 s, 1 H);8.07 (broad s, 1 H); 9.88 (s, 1 H) II-18 Methyl 7-[2- 5/6.4 3.17 (s, 3H), 3.8 (m, 1 H), A (difluoromethoxy)phenyl]-2- 3.81 (s, 3 H), 7.35 (m,2 H), 7.6 (m, 2 399 (methylsulfinyl)thieno[3,2- H), 9.9 (s, 1 H) 0.78d]pyrimidine-6-carboxylate II-19 Methyl 2-(methylsulfonyl)-7-[2- 4/6.33.37 (s, 3 H); 3.82 (s, 3 H); 7.51 A (trifluoromethoxy)- to 7.72 (m, 4H); 9.99 (s, 1 H) 433 phenyl]thieno[3,2-d]pyrimidine- 0.95 6-carboxylateII-20 Methyl 2-(methylsulfonyl)-7-[3- 4/6.3 3.39 (s, 3 H); 3.84 (s, 3H); A (trifluoromethoxy)- 7.52 (m, 1 H); 7.62 to 7.69 (m, 3 H); 433phenyl]thieno[3,2-d]pyrimidine- 9.96 (s, 1 H) 0.99 6-carboxylate II-21Methyl 7-(2-methylphenyl)-2- 3 2.02 (s, 3 H); 3.34 (s, 3 H); A(methylsulfonyl)thieno[3,2- 3.80 (s, 3 H); 7.20 to 7.42 (m, 4 H); 363d]pyrimidine-6-carboxylate 9.95 (s, 1 H) 0.87 II-22 Methyl7-(2-cyanophenyl)-2- 3 3.37 (s, 3 H); 3.85 (s, 3 H); A(methylsulfonyl)thieno[3,2- 7.74 (m, 2 H); 7.89 (t, J = 7.8 Hz, 1 H);374 d]pyrimidine-6-carboxylate 8.04 (d, J = 7.8 Hz, 1 H); 10.01 (s, 0.731 H) II-23 Methyl 7-(3-cyanophenyl)-2- 4/6.3 3.40 (s, 3 H); 3.86 (s, 3H); A (methylsulfonyl)thieno[3,2- 7.75 (t, J = 7.8 Hz, 1 H); 7.95 (td, J= 1.5 374 d]pyrimidine-6-carboxylate and 7.8 Hz, 1 H); 7.99 (td, J = 1.50.77 and 7.8 Hz, 1 H); 8.13 (t, J = 1.5 Hz, 1 H); 9.97 (s, 1 H) II-24Methyl 7-[2- 3 A (methylsulfinyl)phenyl]-2- 411(methylsulfonyl)thieno[3,2- 0.57 and 0.59 d]pyrimidine-6-carboxylateII-25 Methyl 7-[3- 3 A (methylsulfinyl)phenyl]-2- 411(methylsulfonyl)thieno[3,2- 0.88 d]pyrimidine-6-carboxylate II-26 Methyl7-[2-fluoro-5- 3 3.39 (s, 3 H); 3.85 (s, 3 H); A(hydroxymethyl)phenyl]-2- 4.56 (d, J = 5.7 Hz, 2 H); 5.30 (t, J = 5.7Hz, 397 (methylsulfonyl)thieno[3,2- 1 H); 7.32 (m, 1 H); 7.47 0.68d]pyrimidine-6-carboxylate to 7.57 (m, 2 H); 9.97 (s, 1 H) II-27 Methyl2-(methylsulfonyl)-7- 3 3.45 (s, 3 H); 3.89 (s, 3 H); C(thiophen-3-yl)thieno[3,2- 7.52 (dd, J = 1.3 and 5.0 Hz, 1 H); 355d]pyrimidine-6-carboxylate 7.66 (dd, J = 3.1 and 5.0 Hz, 1 H); 4.35 8.08(dd, J = 1.3 and 3.1 Hz, 1 H); 9.93 (s, 1 H) II-28 Methyl2-(methylsulfonyl)-7- 4/6.3 B (thiophen-2-yl)thieno[3,2- 355d]pyrimidine-6-carboxylate 1.33 II-29 Methyl 7-(1-methyl-1H-pyrazol-4/6.1 A 5-yl)-2-(methylsulfonyl)- 353 thieno[3,2-d]pyrimidine-6- 0.55carboxylate II-30 Methyl 2-(methylsulfonyl)-7-(1- 5/6.1 Doxidopyridin-2-yl)thieno[3,2- 365 d]pyrimidine-6-carboxylate 2.45 II-31Methyl 7-(2-methoxypyridin-3- 3 3.38 (s, 3 H); 3.79 (s, 3 H); Ayl)-2-(methylsulfonyl)- 3.83 (s, 3 H); 7.19 (dd, J = 5.1 and 7.3 Hz, 380thieno[3,2-d]pyrimidine-6- 1 H); 7.90 (dd, J = 2.0 and 7.3 Hz, 0.71carboxylate 1 H); 8.32 (dd, J = 2.0 and 5.1 Hz, 1 H); 9.95 (s, 1 H)II-32 Methyl 7-(1-{[(2-methylpropan- 3 D 2-yl)oxy]carbonyl}-1H-pyrrol-2-438 yl)-2- 4.01 (methylsulfonyl)thieno[3,2- d]pyrimidine-6-carboxylateII-33 Methyl 7-(5-fluoro-2- 3 2.90 (s, 3 H); 3.88 (s, 3 H); Amethoxypyridin-4-yl)-2- 3.92 (s, 3 H); 7.10 (d, J = 4.8 Hz, 1 H); 382(methylsulfonyl)thieno[3,2- 8.31 (broad s, 1 H); 9.91 (s, 1 H) 0.69d]pyrimidine-6-carboxylate II-34 Methyl 7-(1-methyl-1H-pyrazol- 4/6.23.51 (s, 3 H); 3.95 (s, 3 H); A 4-yl)-2- 3.99 (s, 3 H); 8.21 (s, 1 H);8.49 (s, 1 353 (methylsulfonyl)thieno[3,2- H); 9.90 (s, 1 H) 0.60d]pyrimidine-6-carboxylate II-35 Methyl 2-(methylsulfonyl)-7- 4/6.2 3.50(s, 3 H); 3.95 (s, 3 H); A (1H-pyrazol-4-yl)thieno[3,2- 6.75 (broad m, 1H); 8.30 (broad m, 1 339 d]pyrimidine-6-carboxylate H); 9.90 (s, 1 H);13.20 (broad m, 0.54 1 H) II-36 Methyl 7-(5-fluoro-2- 3 3.40 (s, 3 H);3.79 (s, 3 H); A methoxypyridin-3-yl)-2- 3.86 (s, 3 H); 7.97 (dd, J =3.0 and 8.5 Hz, 398 (methylsulfonyl)thieno[3,2- 1 H); 8.32 (d, J = 3.0Hz, 1 0.80 d]pyrimidine-6-carboxylate H); 9.97 (s, 1 H) II-37 Methyl7-(6-methoxypyridin-2- 5/6.4 2.95 (s, 3 H); 3.81 (s, 3 H); Ayl)-2-(methylsulfinyl)thieno[3,2- 3.88 (s, 3 H); 6.92 (d, J = 8.0 Hz, 1H); 364 d]pyrimidine-6-carboxylate 7.69 (d, J = 8.0 Hz, 1 H); 7.91 (t, J= 8.0 Hz, 0.66 1 H); 9.89 (s, 1 H) II-38 Methyl 7-(1-methyl-1H-pyrrol- 33.41 (s, 3 H); 3.48 (s, 3 H); A 2-yl)-2-(methylsulfonyl)- 3.88 (s, 3 H);6.19 (dd, J = 2.8 and 3.8 Hz, 352 thieno[3,2-d]pyrimidine-6- 1 H); 6.32(dd, J = 2.0 and 3.8 Hz, 0.74 carboxylate 1 H); 7.01 (dd, J = 2.0 and2.8 Hz, 1 H); 9.92 (s, 1 H) II-39 Methyl 7-(2-methylpyridin-3- 3 2.21(s, 3 H); 3.35 (s, 3 H); A yl)-2-(methylsulfonyl)- 3.81 (s, 3 H); 7.36(dd, J = 5.1 and 7.3 Hz, 364 thieno[3,2-d]pyrimidine-6- 1 H); 7.70 (dd,J = 2.0 and 7.3 Hz, 0.33 carboxylate 1 H); 8.58 (dd, J = 2.0 and 5.1 Hz,1 H); 9.98 (s, 1 H) II-40 Methyl 7-(furan-2-yl)-2- 4/6.1 3.51 (s, 3 H);3.97 (s, 3 H); A (methylsulfonyl)thieno[3,2- 6.78 (dd, J = 1.5 and 3.0Hz, 1 H); 339 d]pyrimidine-6-carboxylate 7.41 (dd, J = 0.8 and 3.0 Hz, 1H); 0.74 7.97 (dd, J = 0.8 and 1.5 Hz, 1 H); 9.93 (s, 1 H) II-41 Methyl7-{5-[({[(2- 4/6.1 1.40 (s, 9 H); 3.51 (s, 3 H); A methylpropan-2- 3.98(s, 3 H); 4.22 (broad d, J = 5.5 Hz, 468yl)oxy]carbonyl}amino)methyl]furan- 2 H); 6.48 (d, J = 3.5 Hz, 1 H);0.92 2-yl}-2- 7.38 (d, J = 3.5 Hz, 1 H); 9.91 (s,(methylsulfonyl)thieno[3,2- 1 H); 13.30 (broad m, 1 H)d]pyrimidine-6-carboxylate II-42 Methyl 7-(2-methylfuran-3-yl)- 4/6.2 D2-(methylsulfinyl)thieno[3,2- 337 d]pyrimidine-6-carboxylate 3.39 II-43Methyl 7-(1-{[(2-methylpropan- 3 1.60 (s, 9 H); 3.50 (s, 3 H); A2-yl)oxy]carbonyl}-1H-pyrrol-3- 3.93 (s, 3 H); 6.89 (dd, J = 2.0 and 3.8Hz, 438 yl)-2-(methylsulfonyl)- 1 H); 7.39 (dd, J = 2.8 and 3.8 Hz, 1.03thieno[3,2-d]pyrimidine-6- 1 H); 8.15 (dd, J = 2.0 and 2.8 Hz,carboxylate 1 H); 9.91 (s, 1 H) II-44 Methyl 7-(2-ethoxypyridin-3- 31.15 (t, J = 7.1 Hz, 3 H); 3.40 (s, 3 A yl)-2-(methylsulfonyl)- H); 3.83(s, 3 H); 4.29 (q, J = 7.0 Hz, 394 thieno[3,2-d]pyrimidine-6- 2 H); 7.19(dd, J = 5.1 and 7.3 Hz, 0.79 carboxylate 1 H); 7.91 (dd, J = 2.0 and7.3 Hz, 1 H); 8.30 (dd, J = 2.0 and 5.1 Hz, 1 H); 9.96 (s, 1 H) II-45Methyl 7-(2-methoxy-5- 3 2.30 (s, 3 H); 3.40 (s, 3 H); Amethylpyridin-3-yl)-2- 3.75 (s, 3 H); 3.83 (s, 3 H); 7.74 (d, J = 3.0Hz, 394 (methylsulfonyl)thieno[3,2- 1 H); 8.11 (d, J = 3.0 Hz, 0.78d]pyrimidine-6-carboxylate 1 H); 9.94 (s, 1 H) II-46 Methyl7-(1-methyl-1H-pyrazol- 4/6.1 3.47 (s, 3 H); 3.88 (s, 3 H); A3-yl)-2-(methylsulfonyl)- 3.92 (s, 3 H); 6.89 (d, J = 2.0 Hz, 1 H); 353thieno[3,2-d]pyrimidine-6- 7.87 (d, J = 2.0 Hz, 1 H); 9.91 (s, 0.56carboxylate 1 H) II-47 Methyl 7-(2-methoxy-6- 3 2.50 (s partiallymasked, 3 H); A methylpyridin-3-yl)-2- 3.39 (s, 3 H); 3.77 (s, 3 H); 394(methylsulfonyl)thieno[3,2- 3.83 (s, 3 H); 7.05 (d, J = 7.3 Hz, 1 H);0.84 d]pyrimidine-6-carboxylate 7.79 (d, J = 7.3 Hz, 1 H); 9.92 (s, 1 H)II-48 Methyl 7-(3-methoxypyridin-2- 5/6.4 2.86 (s, 3 H); 3.75 (s, 3 H);A yl)-2-(methylsulfinyl)thieno[3,2- 3.78 (s, 3 H); 7.57 (dd, J = 8.0 and5.0 Hz, 364 d]pyrimidine-6-carboxylate 1 H); 7.71 (d, J = 8.0 Hz, 1 H);0.69 8.32 (t, J = 5.0 Hz, 1 H); 9.89 (s, 1 H) II-49 Methyl7-(6-methylpyridin-3- 3 2.58 (s, 3 H); 3.4 (s, 3 H); 3.85 (s, Dyl)-2-(methylsulfinyl)thieno[3,2- 3 H); 7.42 (d, J = 7 Hz, 1 H); 364d]pyrimidine-6-carboxylate 7.93 (dd, J = 7 and 1 Hz, 1 H); 8.65 (d, 2.33J = 1 Hz, 1 H); 9.95 (s, 1 H) II-50 Methyl 2-(methylsulfonyl)-7- 5/6.1 A(pyridin-2-yl)thieno[3,2- 350 d]pyrimidine-6-carboxylate 0.78

III—Preparation of the Compounds of Formula (IIIa) (Example 8) Method 1:4-(1-Methylpiperidin-4-yl)-2-(propan-2-yloxy)aniline

A mixture of 10.0 g of 4-bromo-2-fluoro-1-nitrobenzene, 44.4 g ofcaesium carbonate and 100 ml of isopropanol is heated at 85° C. (bath)for 1 h 30, and then left to cool to ambient temperature. The mixture isconcentrated under vacuum and the residue is taken up with 400 ml ofwater and 300 ml of ethyl acetate. The aqueous phase is extracted with100 ml of ethyl acetate and the combined organic phases are washed twicewith 200 ml of water. The organic phases are dried over magnesiumsulfate and concentrated under vacuum, so as to obtain 11.59 g of crude4-bromo-1-nitro-2-(propan-2-yloxy)benzene in the form of a yellow oilwhich crystallizes. TLC: Rf=0.52 (dichloromethane/heptane (1/1)).

A mixture of 10.0 g of 4-bromo-1-nitro-2-(propan-2-yloxy)benzene, 5.78 gof 4-pyridylboronic acid, 12.2 g of sodium carbonate and 1.0 g ofbis(triphenylphosphine)dichloropalladium, in 200 ml of dioxane and 35 mlof water, is heated at 110° C. (bath) for 9 h. The mixture is dilutedwith ethyl acetate and water. The aqueous phase is extracted twice withethyl acetate and then with dichloromethane. The combined organic phasesare dried over magnesium sulfate and concentrated under vacuum. Theresidue is purified on 330 g of silica, elution being carried out withethyl acetate/heptane (1/1 to 4/1), so as to obtain 7.35 g of4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridine in the form of a paleyellow solid.

A mixture of 7.35 g of 4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridine and16.1 g of methyl iodide in 150 ml of acetonitrile is heated at 50° C.(bath) for 1 h. 2.5 ml of methyl iodide are added and the heating iscontinued for 1 h 50. The mixture is then concentrated under vacuum, soas to obtain 11.1 g of1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodide.

A solution of 10 g of1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodide in 280 mlof methanol is hydrogenated in an autoclave on 2.9 g of platinum oxidehydrate, at a hydrogen pressure of 15 bar and at ambient temperature for4 h. The catalyst is removed by filtration on Clarcel and the mixture isconcentrated under vacuum. The residue is taken up in 200 ml of ethylacetate and washed with 200 ml of 1M sodium hydroxide and then with asaturated sodium chloride solution. The organic phase is dried overmagnesium sulfate and concentrated under vacuum, so as to obtain 6.0 gof 4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)aniline.

Method 2: 2-Methylpropan-2-yl4-[4-amino-3-(propan-2-yloxy)phenyl]-2-ethylpiperidine-1-carboxylate

0.89 ml of diisopropylamine is introduced into 5 ml of THF. Aftercooling to −78° C., 2.45 ml of 2.5 M n-BuLi in hexane are added and themixture is stirred for 15 minutes at −78° C. A solution of 1 g of1-boc-2-ethylpiperidin-4-one in solution in 10 ml of THF is addeddropwise. The reaction medium is stirred for 15 minutes at −78° C. andthen N-phenylbis(trifluoromethanesulfonimide) in solution in 15 ml ofTHF is added. The reaction medium is brought back to ambient temperatureand stirred for 16 hours at this temperature. The mixture is poured into15 ml of a saturated aqueous sodium bicarbonate solution and thenextracted with ethyl acetate, dried over magnesium sulfate, filtered andconcentrated under reduced pressure. Purification is carried out byflash chromatography on silica gel (40-63 μm), elution being carried outwith a dichloromethane/methanol (98/2) mixture. 870 mg of2-methylpropan-2-yl6-ethyl-4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylateare obtained in the form of a pale yellow oil.

A mixture of 5 g of 4-bromo-1-nitro-2-(propan-2-yloxy)benzene, 5.65 g ofpotassium acetate, 5.85 g of bis(pinacolato)diborane and 704 mg of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in 115 ml ofdioxane is heated at 90° C. for 4 h 30. The reaction medium is pouredinto 250 ml of water and then extracted with twice 50 ml of water. Thecombined organic phases are dried over magnesium sulfate, filtered andevaporated. Purification is carried out by flash chromatography onsilica gel (40-63 μm), elution being carried out with adichloromethane/heptane (80/20) mixture. 2.5 g of4,4,5,5-tetramethyl-2-[4-nitro-3-(propan-2-yloxy)phenyl]-1,3,2-dioxaborolaneare obtained in the form of a yellow oil.

450 mg of 2-methylpropan-2-yl6-ethyl-4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylateare introduced into 27 ml of 1,4-dioxane. After sparging for 10 min withargon in the reaction medium, 843 mg of4,4,5,5-tetramethyl-2-[4-nitro-3-(propan-2-yloxy)phenyl]-1,3,2-dioxaborolane,100 mg of lithium chloride, 1.46 ml of a 2N solution of sodium carbonateand 203 mg of tetrakis(triphenylphosphine)palladium(0) are added. Thereaction mixture is heated at 80° C. for 2 h. After cooling, the mixtureis run into water, extracted with ethyl acetate, washed with a saturatedsodium chloride solution, dried over magnesium sulfate, filtered andconcentrated under reduced pressure. Purification is carried out byflash chromatography on silica gel (40-63 μm), elution being carried outwith a mixture of heptane and ethyl acetate (90/10), and 470 mg of2-methylpropan-2-yl6-ethyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]-3,6-dihydropyridine-1(2H)-carboxylateare obtained in the form of a yellow oil.

In a microwave tube, 470 mg of 2-methylpropan-2-yl6-ethyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]-3,6-dihydropyridine-1(2H)-carboxylateare introduced into 20 ml of methanol. 456 mg of ammonium formate and385 mg of Pd/C (10%) are added. The reaction medium is microwave-heatedat 80° C. for 5 minutes. The mixture is filtered on Clarcel and theClarcel is rinsed with methanol. The filtrate is concentrated underreduced pressure. The residue is taken up with 30 ml of ethyl acetateand 3 ml of water. The organic phase is dried over magnesium sulfate,filtered and concentrated under reduced pressure, so as to obtain 370 mgof 2-methylpropan-2-yl4-[4-amino-3-(propan-2-yloxy)phenyl]-2-ethylpiperidine-1-carboxylate inthe form of a colourless oil.

Method 3:4-(5-Methoxy-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(propan-2-yloxy)aniline

A mixture of 2.5 g of 4-bromo-1-nitro-2-(propan-2-yloxy)benzene, 2.58 gof 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine,9.4 g of caesium carbonate and 703 mg of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in 27 ml ofdioxane and 8.8 ml of water, is microwave-heated at 130° C. for 20minutes. The mixture is diluted with ethyl acetate and water. Theaqueous phase is extracted with ethyl acetate (2×) and then withdichloromethane (2×10 ml). The combined organic phases are dried overmagnesium sulfate and concentrated under vacuum. The residue is purifiedon 100 g of silica, elution being carried out with heptane/ethyl acetate(50/50 to 0/100), so as to obtain 2.63 g of3-methoxy-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridine in the form of abrown solid.

A mixture of 3.41 g of3-methoxy-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridine and 1.33 ml ofmethyl iodide in 55 ml of acetone is heated at 50° C. (bath) for 3 h 30.147 μl of methyl iodide are added and the heating is continued at 50° C.for 50 minutes. The mixture is then concentrated under vacuum, so as toobtain 5.13 g of3-methoxy-1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodidein the form of a yellow solid.

672 mg of NaBH₄ are added, in portions, to a suspension of 5.09 g of3-methoxy-1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodidein 90 ml of ethanol brought to 5° C., the reaction medium is stirred for30 minutes at ambient temperature. 50 ml of water and 100 ml of ethylacetate are added. The two phases are separated, and the aqueous phaseis washed with twice 50 ml of ethyl acetate. The combined organic phasesare dried over magnesium sulfate, filtered and evaporated. Purificationis carried out by flash chromatography on silica gel (40-63 μm), elutionbeing carried out with a mixture of dichloromethane and acetone (95/5 to80/20). 2.78 g of5-methoxy-1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]-1,2,3,6-tetrahydropyridineare obtained in the form of a brown oil.

747 mg of zinc are added to a solution of 500 mg of5-methoxy-1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]-1,2,3,6-tetrahydropyridinein 8 ml of acetic acid. The reaction medium is stirred for 1 hour atambient temperature and then filtered on Clarcel. The Clarcel is rinsedwith 8 ml of acetic acid, then 10 ml of ethanol and then of ethylacetate. The filtrate is evaporated under reduced pressure and then theresidue is taken up in 10 ml of ethyl acetate, 5 ml of water and 10 mlof a saturated aqueous sodium bicarbonate solution. 20 ml of ethylacetate are added and the two phases are separated. The aqueous phase isextracted with ethyl acetate (2×10 ml). The combined organic phases arewashed with a saturated aqueous sodium chloride solution, dried overmagnesium sulfate and concentrated under vacuum. The residue is purifiedon 25 g of silica, elution being carried out withdichloromethane/acetone (100/0 to 95/5), so as to obtain 140 mg of4-(5-methoxy-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(propan-2-yloxy)anilinein the form of a brown oil.

Method 4: 4-[4-Amino-3-(propan-2-yloxy)phenyl]-1-methylpiperidin-3-ol

7.55 g of ammonium formate and 1.5 g of Pd/C (10%) are added to asolution of 5.75 g of3-methoxy-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridine in 100 ml ofmethanol. The reaction medium is microwave-heated at 80° C. for 5minutes. The mixture is filtered on Clarcel, and the Clarcel is rinsedwith methanol. The filtrate is concentrated under reduced pressure. Theresidue is taken up with 60 ml of ethyl acetate and 20 ml of water. The2 phases are separated, and the aqueous phase is extracted with twice 20ml of ethyl acetate. The combined organic phases are dried overmagnesium sulfate, filtered and evaporated, so as to give 5.35 g of4-(3-methoxypyridin-4-yl)-2-(propan-2-yloxy)aniline in the form of abrown gum.

85 ml of a saturated aqueous sodium bicarbonate solution and then 3.81ml of benzyl chloroformate are added to a solution of 4.6 g of4-(3-methoxypyridin-4-yl)-2-(propan-2-yloxy)aniline in 115 ml of THF.The reaction medium is stirred overnight at ambient temperature and then3.81 ml of benzyl chloroformate are added and the reaction medium isstirred at ambient temperature for 2 hours. 2.54 ml of benzylchloroformate are added and the reaction medium is stirred for a further2 hours at ambient temperature. The reaction medium is poured into 100ml of ethyl acetate and 50 ml of water. The two phases are separated andthe aqueous phase is extracted with twice 50 ml of ethyl acetate. Thecombined organic phases are dried over magnesium sulfate, filtered andevaporated under reduced pressure. The residue is purified on 100 g ofsilica, elution being carried out with dichloromethane/acetone (100/0 to95/5), so as to give 3.12 g of benzyl[4-(3-methoxypyridin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate in theform of a colourless oil.

A mixture of 3.58 g of benzyl[4-(3-methoxypyridin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate and 1.14ml of methyl iodide in 107 ml of acetone is heated at 50° C. (bath) for1 h. 568 μl of methyl iodide are added and the heating is continued at50° C. for 30 minutes. The mixture is then concentrated under vacuum, soas to give 4.57 g of4-[4-{[(benzyloxy)carbonyl]amino}-3-(propan-2-yloxy)phenyl]-3-methoxy-1-methylpyridiniumiodide in the form of a yellow solid.

486 mg of NaBH₄ are added, in portions, to a suspension of 4.57 g of4-[4-{[(benzyloxy)carbonyl]amino}-3-(propan-2-yloxy)phenyl]-3-methoxy-1-methylpyridiniumiodide in 100 ml of ethanol brought to 5° C. The reaction medium isstirred for 1 h 30 at ambient temperature. 50 ml of water, 50 ml of asaturated aqueous sodium bicarbonate solution and 100 ml of ethylacetate are added. The two phases are separated, and the aqueous phaseis washed with twice 50 ml of ethyl acetate. The combined organic phasesare dried over magnesium sulfate, filtered and evaporated. Purificationis carried out by flash chromatography on silica gel (40-63 μm), elutionbeing carried out with a mixture of dichloromethane and (MeOH+10% NH₄OH)(99/1 to 90/10). 1.87 g of benzyl[4-(5-methoxy-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(propan-2-yloxy)phenyl]carbamateare obtained in the form of an orangey-coloured oil.

30 ml of a 6N aqueous hydrochloric acid solution are added to a solutionof 1.77 g of benzyl[4-(5-methoxy-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(propan-2-yloxy)phenyl]carbamatein 60 ml of THF. The reaction medium is heated at 50° C. for 2 h 30 andthen evaporated to dryness. The residue is taken up in 15 ml of water, 5ml of a saturated aqueous sodium carbonate solution and 50 ml of ethylacetate. The two phases are separated, and the aqueous phase is washedwith twice 15 ml of ethyl acetate. The combined organic phases are driedover magnesium sulfate, filtered and evaporated, so as to give 1.7 g ofbenzyl[4-(1-methyl-3-oxopiperidin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate inthe form of a brown gum.

486 mg of NaBH₄ are added, in portions, to a suspension of 700 mg ofbenzyl[4-(1-methyl-3-oxopiperidin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate in35 ml of ethanol brought to 5° C. The reaction medium is stirred atambient temperature for 50 minutes. 4 ml of water, 15 ml of a saturatedaqueous sodium chloride solution and 40 ml of ethyl acetate are added.The two phases are separated, and the aqueous phase is washed with twice20 ml of ethyl acetate. The combined organic phases are dried overmagnesium sulfate, filtered and evaporated. Purification is carried outby flash chromatography on silica gel (40-63 μm), elution being carriedout with a mixture of dichloromethane and (MeOH+10% NH₄OH) (99/1 to90/10). 183 mg of benzyl[4-(3-hydroxy-1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate(trans diastereoisomers) and 183 mg of benzyl[4-(3-hydroxy-1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate(cis diastereoisomers) are obtained.

178 mg of benzyl[4-(3-hydroxy-1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate(mixture of the cis diastereoisomers) are dissolved in 45 ml ofmethanol. The solution is filtered on 0.45 μm Acrodisc and thenhydrogenated in an H-cube (Pd/C 10% cartridge and P H₂=1 atm). Thereaction medium is evaporated to dryness under reduced pressure, so asto give 111 mg of4-[4-amino-3-(propan-2-yloxy)phenyl]-1-methylpiperidin-3-ol in the formof an orangey-coloured solid (mixture of the cis diastereoisomers).

179 mg of benzyl[4-(3-hydroxy-1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate(mixture of the trans diastereoisomers) are dissolved in 45 ml ofmethanol. The solution is filtered on 0.45 μm Acrodisc and thenhydrogenated in an H-cube (Pd/C 10% cartridge and P H₂=1 atm). Thereaction medium is evaporated to dryness under reduced pressure, so asto give 127 mg of4-[4-amino-3-(propan-2-yloxy)phenyl]-1-methylpiperidin-3-ol in the formof a brown gum (mixture of the trans diastereoisomers).

Method 5: 2-Methylpropan-2-yl4-[4-amino-3-(propan-2-yloxy)phenyl]piperidine-1-carboxylate

A mixture of 3.26 g of 4-bromo-1-nitro-2-(propan-2-yloxy)benzene, 4.65 gof 2-methylpropan-2-yl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate,12.5 ml of a 3M solution of sodium carbonate and 350 mg ofbis(triphenylphosphine)dichloropalladium(II) in 41 ml of dioxane isrefluxed for 1 h 30. The mixture is diluted with 150 ml of water and 200ml of ethyl acetate. The aqueous phase is extracted three times with 200ml of ethyl acetate. The combined organic phases are washed with 100 mlof a saturated sodium chloride solution, dried over magnesium sulfateand concentrated under vacuum. The residue is purified on 600 g ofsilica, elution being carried out with dichloromethane/ethyl acetate(99/1), so as to give 2.95 g of 2-methylpropan-2-yl4-[4-nitro-3-(propan-2-yloxy)phenyl]-3,6-dihydropyridine-1(2H)-carboxylatein the form of a yellow solid.

A solution of 2.76 g of 2-methylpropan-2-yl4-[4-nitro-3-(propan-2-yloxy)phenyl]-3,6-dihydropyridine-1(2H)-carboxylatein 60 ml of methanol is hydrogenated on 300 mg of palladium-on-carbon(10%) at a pressure of 10 bar and at ambient temperature for 3 h. Thecatalyst is removed by filtration on Celite and the filtrate isevaporated to dryness so as to obtain 2.44 g of 2-methylpropan-2-yl4-[4-amino-3-(propan-2-yloxy)phenyl]piperidine-1-carboxylate in the formof a pink powder.

Method 6: 4-(4-Methylpiperazin-1-yl)-2-(propan-2-yloxy)aniline

A mixture of 18.0 g of 5-fluoro-2-nitrophenol, 29.0 g of caesiumcarbonate and 13.7 ml of 2-iodopropane in 119 ml of DMF is stirred atambient temperature overnight. The mixture is concentrated under vacuumand the residue is taken up with 250 ml of water and extracted twicewith 250 ml of ethyl acetate. The organic phases are washed twice with200 ml of a saturated sodium chloride solution, dried over magnesiumsulfate and concentrated under vacuum, so as to obtain 17 g of crudeproduct. The crude product is purified on 400 g of silica, elution beingcarried out with cyclohexane/ethyl acetate (95/5), so as to obtain 13.0g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene in the form of a lightyellow oil.

A mixture of 10.0 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 10.0g of 1-methylpiperazine and 10.4 g of potassium carbonate in 93 ml ofDMSO is stirred at ambient temperature overnight. The mixture is dilutedwith 160 ml of water and extracted three times with 150 ml of ethylacetate. The organic phases are dried over magnesium sulfate andconcentrated under vacuum. The residue is purified on 200 g of silica,elution being carried out with dichloromethane/methanol (98/2 then95/5), so as to obtain 13.6 g of1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazine in the form of ayellow oil.

A mixture of 9.0 g of1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazine, 19.3 g ofhydrazine hydrate and 1.7 g of 10% palladium-on-carbon in 205 ml ofethanol is heated at 80° C. (bath) for 45 min. The mixture is filteredand the filtrate is concentrated under vacuum, so as to obtain 13 g ofan orangey-coloured oil. The residue is purified on 300 g of silica,elution being carried out with dichloromethane/methanol (95/5), so as toobtain 7.1 g of 4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)aniline inthe form of a brown oil.

Method 7: 1-[4-Amino-3-(propan-2-yloxy)phenyl]piperidin-4-yl acetate

4.75 g of di-tert-butyl dicarbonate are added to a mixture of 2 g of4-hydroxypiperidine in 4 ml of water and 13.8 ml of a 2N aqueous sodiumhydroxide solution. The reaction medium is stirred at ambienttemperature for 2 hours and then 50 ml of chloroform are added. The twophases are separated and the organic phase is washed with an aqueous 25%NH₄OH solution and then with a saturated aqueous sodium chloridesolution. The organic phase is dried over magnesium sulfate, filteredand evaporated, so as to give 4 g of 2-methylpropan-2-yl4-hydroxypiperidine-1-carboxylate in the form of a colourless oil.

2.84 g of acetic anhydride are added to a solution of 4.0 g of2-methylpropan-2-yl 4-hydroxypiperidine-1-carboxylate in 6 ml ofpyridine. The reaction medium is stirred for 5 hours at ambienttemperature and then concentrated to dryness. The residue is taken up indichloromethane and an aqueous 25% NH₄OH solution. The two phases areseparated and the organic phase is washed with a saturated aqueoussodium chloride solution, dried over magnesium sulfate, filtered andevaporated. Purification is carried out by flash chromatography onsilica gel (40-63 μm), elution being carried out with a mixture ofdichloromethane and MeOH (95/5), so as to obtain 3 g of2-methylpropan-2-yl 4-(acetyloxy)piperidine-1-carboxylate in the form ofa colourless oil.

3 ml of trifluoroacetic acid are added to a solution of 3.18 g of2-methylpropan-2-yl 4-(acetyloxy)piperidine-1-carboxylate in 40 ml ofdichloromethane, cooled to 0° C. The reaction medium is stirred for 1hour at 0° C. and then 1 hour at ambient temperature. 5 ml oftrifluoroacetic acid are added and the reaction medium is stirred for 30minutes at ambient temperature. The reaction medium is evaporated todryness under reduced pressure, and the resulting product is taken upwith dichloromethane and an aqueous 1% NH₄OH solution. The organic phaseis washed with a saturated aqueous sodium chloride solution, dried overmagnesium sulfate, filtered and evaporated, so as to give 175 mg ofpiperidin-4-yl acetate in the form of a yellow oil.

A mixture of 1 g of 4-bromo-1-nitro-2-(propan-2-yloxy)benzene, 1.19 g ofpiperidin-4-yl acetate, 5.01 g of caesium carbonate, 86 mg of palladiumacetate and 334 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene,in 50 ml of dioxane, is refluxed for 3 hours. The mixture is dilutedwith ethyl acetate and water. The aqueous phase is extracted with ethylacetate (2×). The combined organic phases are dried over magnesiumsulfate and concentrated under vacuum. The residue is purified onsilica, elution being carried out with cyclohexane/ethyl acetate (80/80to 50/50), so as to give 530 mg1-[4-nitro-3-(propan-2-yloxy)phenyl]piperidin-4-yl acetate in the formof a brown solid.

622 mg of ammonium formate and 525 mg of Pd/C (10%) are added to asolution of 530 mg of 1-[4-nitro-3-(propan-2-yloxy)phenyl]piperidin-4-ylacetate in 13 ml of methanol. The reaction medium is microwave-heated at80° C. for 5 minutes. The mixture is filtered on Clarcel, and theClarcel is rinsed with methanol. The filtrate is concentrated underreduced pressure. The residue is taken up with 20 ml of ethyl acetate, 2ml of water and 8 ml of a saturated aqueous sodium chloride solution.The two phases are separated and the aqueous phase is washed with 3times 10 ml of ethyl acetate. The combined organic phases are dried overmagnesium sulfate, filtered and evaporated. The residue is purified onsilica, elution being carried out with dichloromethane/MeOH (95/5), soas to give 190 mg of 1-[4-amino-3-(propan-2-yloxy)phenyl]piperidin-4-ylacetate in the form of a brown oil.

Method 8: 2-(Propan-2-yloxy)-4-(1H-1,2,4-triazol-1-yl)aniline

A mixture of 1 g of 4-bromo-1-nitro-2-(propan-2-yloxy)benzene, 319 mg oftriazole, 110 mg of copper (I) iodide, 585 mg of potassium carbonate and84 mg of 8-hydroxyquinoline in 8 ml of DMSO is stirred overnight atambient temperature and then heated at 120° C. for 3 hours. The reactionmedium is poured into 10 ml of an aqueous 25% NH₄OH solution, 40 ml ofwater and 10 ml of ethyl acetate. The mixture is stirred for 30 minutesat ambient temperature and then the two phases are separated. Theaqueous phase is washed with twice 40 ml of ethyl acetate. The combinedorganic phases are dried over magnesium sulfate, filtered andevaporated. Purification is carried out by flash chromatography onsilica gel (40-63 μm), elution being carried out with a mixture ofdichloromethane and acetone (100/0 to 95/5). 695 mg of1-[4-nitro-3-(propan-2-yloxy)phenyl]-1H-1,2,4-triazole are obtained inthe form of a beige solid.

965 mg of ammonium formate and 172 mg of Pd/C (10%) are added to asolution of 691 mg of1-[4-nitro-3-(propan-2-yloxy)phenyl]-1H-1,2,4-triazole in 14 ml ofmethanol. The reaction medium is microwave-heated at 80° C. for 5minutes. The mixture is filtered on Clarcel, and the Clarcel is rinsedwith methanol. The filtrate is concentrated under reduced pressure. Theresidue is taken up with 20 ml of ethyl acetate, 2 ml of water and 8 mlof a saturated aqueous sodium chloride solution. The two phases areseparated and the aqueous phase is washed with 3 times 10 ml of ethylacetate. The combined organic phases are dried over magnesium sulfate,filtered and evaporated, so as to give 589 mg of2-(propan-2-yloxy)-4-(1H-1,2,4-triazol-1-yl)aniline in the form of abrown oil.

Method 9:4-[3-(2-Methoxyethyl)-4-methylpiperazin-1-yl]-2-(propan-2-yloxy)aniline

974 mg of N,N-diisopropylethylamine and 724 mg of2-(1-methylpiperazin-2-yl)ethanol are added to a suspension of 1 g of4-fluoro-1-nitro-2-(propan-2-yloxy)benzene in 10 ml of acetonitrile. Thereaction medium is microwave-heated at 110° C. for 6 hours and thenconcentrated to dryness under reduced pressure. Purification is carriedout by flash chromatography on silica gel (40-63 microns), elution beingcarried out with a mixture of dichloromethane and methanol (100/0) to(90/10). 1.15 g of2-{1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazin-2-yl}ethanolare obtained in the form of a yellow oil.

42 microlitres of mesyl chloride are added to a solution of 160 mg of2-{1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazin-2-yl}ethanolin 2 ml of dichloromethane and 0.2 ml of pyridine. The reaction mediumis stirred at ambient temperature overnight and then concentrated undervacuum, under reduced pressure, so as to give 190 mg of2-{1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazin-2-yl}ethylmethanesulfonate in the form of an orangey-coloured oil.

51.1 mg of sodium methoxide are added to a solution of2-{1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazin-2-yl}ethylmethanesulfonate in 3 ml of methanol. The reaction medium is stirred for10 minutes at ambient temperature and then 30 minutes at 90° C. in amicrowave (CEM). The reaction medium is concentrated to dryness underreduced pressure, and taken up with water and ethyl acetate. Thecombined organic phases are dried over magnesium sulfate, filtered andevaporated. Purification is carried out by flash chromatography onsilica gel (40-63 microns), elution being carried out with a mixture ofdichloromethane and methanol (100/0) to (80/20). 100 mg of2-(2-methoxyethyl)-1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazineare obtained in the form of a yellow oil.

112 mg of ammonium formate and 10 mg of Pd/C (10%) are added to asolution of 100 mg of2-(2-methoxyethyl)-1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazinein 2 ml of methanol. The reaction medium is microwave-heated at 80° C.for 5 minutes. The mixture is filtered on Clarcel and the Clarcel isrinsed with methanol. The filtrate is concentrated under reducedpressure. The residue is taken up with 10 ml of ethyl acetate and 2 mlof water. The two phases are separated, and the aqueous phase is washedwith twice 10 ml of ethyl acetate. The combined organic phases are driedover magnesium sulfate, filtered and evaporated, so as to obtain 80 mgof4-[3-(2-methoxyethyl)-4-methylpiperazin-1-yl]-2-(propan-2-yloxy)anilinein the form of a brown oil.

Method 10: 5-Methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)aniline

24.9 g of caesium carbonate, 745 mg of palladium acetate, 2.88 g of(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and 4.89 g of1-methylpiperazine are added to a solution of 7.62 g of1-chloro-2-methyl-4-nitro-5-(propan-2-yloxy)benzene (prepared accordingto WO2008/073687, p. 31) in 380 ml of dioxane under argon. The mixtureis refluxed for 5.5 h, and then cooled to ambient temperature. Themixture is combined with the crude product of one and the same reactioncarried out on 1.89 g of1-chloro-2-methyl-4-nitro-5-(propan-2-yloxy)benzene under the sameconditions. The mixture is concentrated under vacuum and the residue istaken up with 100 ml of water, 200 ml of ethyl acetate and a littlemethanol. The mixture is filtered on Clarcel and the aqueous phase isextracted twice with 100 ml of ethyl acetate. The combined organicphases are washed with 100 ml of a saturated sodium chloride solution,dried over magnesium sulfate and concentrated under vacuum. The crudeproduct is purified on 340 g of silica, elution being carried out with0-100% of acetone in dichloromethane, so as to obtain 5.60 g of1-methyl-4-[2-methyl-4-nitro-5-(propan-2-yloxy)phenyl]piperazine in theform of a black solid.

Two 20 ml tubes each containing a mixture of 614 mg of1-methyl-4-[2-methyl-4-nitro-5-(propan-2-yloxy)phenyl]piperazine, 185 mgof 10% Pd on carbon and 793 mg of ammonium formate in 10 ml of methanolare microwave-heated at 80° C. (P 6-7 bar) for 5 min. The content of thetubes is combined and filtered on Clarcel. The Clarcel is washed withmethanol and the filtrate is concentrated under vacuum. The residue istaken up with 20 ml of ethyl acetate, 2 ml of water and 8 ml of asaturated sodium chloride solution. The aqueous phase is extracted threetimes with 10 ml of ethyl acetate. The combined organic phases arewashed with 10 ml of a saturated aqueous sodium chloride solution, driedover magnesium sulfate and concentrated under vacuum, so as to obtain1.053 g of 5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)anilinein the form of a light brown solid.

Method 11: 6-(1-Methylpiperidin-4-yl)-4-(propan-2-yloxy)pyridin-3-amine

3.38 g of sodium isopropoxide are added to a solution of 2.6 g of2,4-dichloro-5-nitropyridine in 39 ml of DMF. The reaction medium isstirred at ambient temperature for 1 h 15 and 3.18 g of sodiumisopropoxide are added. The reaction medium is stirred for a further 15minutes and then the mixture is poured into 200 ml of water andextracted with ethyl acetate. The organic phase is dried over magnesiumsulfate, filtered and concentrated under reduced pressure. Purificationis carried out by flash chromatography on silica gel (40-63 microns),elution being carried out with a heptane/ethyl acetate mixture (90/10 to80/20). 1.78 g of 2-chloro-5-nitro-4-(propan-2-yloxy)pyridine areobtained in the form of a pale yellow solid.

800 mg of 2-chloro-5-nitro-4-(propan-2-yloxy)pyridine are introducedinto 62 ml of 1,4-dioxane. After sparging for 10 min with argon in thereaction mixture, 1.25 g of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridinehydrochloride, 6.02 g of caesium carbonate, 6.2 ml of water and 467 mgof bis(triphenylphosphine)palladium(II) dichloride are added. Thereaction mixture is heated at 100° C. for 16 h. After cooling, themixture is run into water and extracted with ethyl acetate. The organicphase is washed with a saturated sodium chloride solution, dried overmagnesium sulfate, filtered and concentrated under reduced pressure.Purification is carried out by flash chromatography on silica gel (40-63microns), elution being carried out with a mixture of dichloromethaneand methanol (90/10 to 80/20). 401 mg of1′-methyl-5-nitro-4-(propan-2-yloxy)-1′,2′,3′,6′-tetrahydro-2,4′-bipyridineare obtained in the form of a yellow gum.

In a microwave tube, 400 mg of1′-methyl-5-nitro-4-(propan-2-yloxy)-1′,2′,3′,6′-tetrahydro-2,4′-bipyridineare introduced into 30 ml of methanol. 546 mg of ammonium formate and333 mg of Pd/C (10%) are added. The reaction medium is microwave-heatedat 80° C. for 5 minutes. The mixture is filtered on Clarcel and theClarcel is rinsed with methanol. The filtrate is concentrated underreduced pressure, so as to give 380 mg of6-(1-methylpiperidin-4-yl)-4-(propan-2-yloxy)pyridin-3-amine in the formof a brown oil.

Method 12: 6-(4-Methylpiperazin-1-yl)-4-(propan-2-yloxy)pyridin-3-amine

383 mg of potassium carbonate and 185 mg of 1-methylpiperazine are addedto a solution of 400 mg of 2-chloro-5-nitro-4-(propan-2-yloxy)pyridinein 3.7 ml of DMSO. The reaction medium is heated for 1 hour at 105° C.After cooling, the mixture is run into water, extracted with ethylacetate, washed with a saturated sodium chloride solution, dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue is taken up in diisopropyl ether, and the insoluble material isfiltered off and dried under vacuum, so as to give 481 mg of1-methyl-4-[5-nitro-4-(propan-2-yloxy)pyridin-2-yl]piperazine in theform of an orangey-coloured solid.

In a microwave tube, 390 mg of1-methyl-4-[5-nitro-4-(propan-2-yloxy)pyridin-2-yl]piperazine areintroduced into 12 ml of methanol. 525 mg of ammonium formate and 210 mgof Pd/C (10%) are added. The reaction medium is microwave-heated at 80°C. for 5 minutes. The mixture is filtered on Clarcel and the Clarcel isrinsed with methanol. The filtrate is concentrated under reducedpressure, so as to give 340 mg of6-(4-methylpiperazin-1-yl)-4-(propan-2-yloxy)pyridin-3-amine in the formof a brown oil.

Method 13: 6-(1-Methylpiperidin-4-yl)-2-(propan-2-yloxy)pyridin-3-amine

1.63 g of 6-chloro-3-nitropyridin-2-ol, 66 ml of heptane, 3.175 g of2-iodopropane and 3.09 g of silver carbonate are introduced. Thereaction medium is microwave-heated at 130° C. for 10 minutes and isthen evaporated to dryness, bound to silica and purified by flashchromatography on silica gel (40-63 μm), elution being carried out witha mixture of heptane and ethyl acetate (90/10). 1.79 g of6-chloro-3-nitro-2-(propan-2-yloxy)pyridine are obtained in the form ofa beige solid.

1 g of 6-chloro-3-nitro-2-(propan-2-yloxy)pyridine is introduced into 78ml of 1,4-dioxane. After sparging for 10 min with argon in the reactionmedium, 2.16 g of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridinehydrochloride, 7.5 g of caesium carbonate, 7.75 ml of water and 584 mgof bis(triphenylphosphine)palladium(II) dichloride are added. Thereaction mixture is heated at 100° C. for 2 h. The mixture isconcentrated under reduced pressure and bound to silica. Purification iscarried out by flash chromatography on silica gel (40-63 μm), elutionbeing carried out with a mixture of dichloromethane and methanol (90/10to 80/20). 500 mg of1′-methyl-5-nitro-6-(propan-2-yloxy)-1′,2′,3′,6′-tetrahydro-2,4′-bipyridineare obtained in the form of an orangey-coloured gum.

In a microwave tube, 300 mg of1′-methyl-5-nitro-6-(propan-2-yloxy)-1′,2′,3′,6′-tetrahydro-2,4′-bipyridineare introduced into 22 ml of methanol. 410 mg of ammonium formate and345 mg of Pd/C (10%) are added. The reaction medium is microwave-heatedat 80° C. for 5 minutes. The mixture is filtered on Clarcel and theClarcel is rinsed with methanol. The filtrate is concentrated underreduced pressure, so as to give 288 mg of6-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)pyridin-3-amine in the formof a brown gum.

Method 14: 6-(4-Methylpiperazin-1-yl)-2-(propan-2-yloxy)pyridin-3-amine

463 mg of potassium carbonate and 224 mg of 1-methylpiperazine are addedto a solution of 484 mg of 6-chloro-3-nitro-2-(propan-2-yloxy)pyridinein 4.45 ml of DMSO. The reaction medium is heated for 1 hour at 105° C.After cooling, the mixture is run into water and extracted with ethylacetate. The organic phase is washed with a saturated sodium chloridesolution, dried over magnesium sulfate, filtered and concentrated underreduced pressure. The residue is taken up in diisopropyl ether and theinsoluble material is filtered off and dried under vacuum, so as to give460 mg of 1-methyl-4-[5-nitro-6-(propan-2-yloxy)pyridin-2-yl]piperazinein the form of a yellow solid.

In a microwave tube, 500 mg of1-methyl-4-[5-nitro-6-(propan-2-yloxy)pyridin-2-yl]piperazine areintroduced into 15 ml of methanol. 675 mg of ammonium formate and 270 mgof Pd/C (10%) are added. The reaction medium is microwave-heated at 80°C. for 5 minutes. The mixture is filtered on Clarcel and the Clarcel isrinsed with methanol. The filtrate is concentrated under reducedpressure, so as to give 512 mg of6-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)pyridin-3-amine in the formof a purple gum.

Method 15: 7-Amino-1-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

2 g of 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are added to a solutionof 25 ml of nitric acid at 70% in water and of 35 ml of sulfuric acidcooled to 0° C. The reaction medium is stirred for 15 minutes at 0° C.and then poured into water (250 ml) and extracted with ethyl acetate.The organic phase is washed with a saturated aqueous sodium bicarbonatesolution and with water, dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The residue is taken up withdiisopropyl ether and the insoluble material is filtered off and driedunder vacuum, so as to give 1.04 g of7-nitro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of a beigesolid.

202 mg of NaH (50%) are added to a solution of 771 mg of7-nitro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 20 ml of DMF. Thereaction medium is stirred for 15 minutes and then 583 mg of iodomethaneare added. The mixture is stirred for 4 hours at ambient temperature andthen run into ice-cold water and extracted with ethyl acetate. Theorganic phase is washed with a saturated sodium chloride solution, driedover magnesium sulfate, filtered and concentrated under reducedpressure. Purification is carried out by flash chromatography on silicagel (40-63 μm), elution being carried out with a heptane/ethyl acetate(80/20 to 50/50) mixture. 275 mg of1-methyl-7-nitro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are obtainedin the form of a yellow solid.

In a microwave tube, 275 mg of1-methyl-7-nitro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are introducedinto 26 ml of methanol. 473 mg of ammonium formate and 398 mg of Pd/C(10%) are added. The reaction medium is microwave-heated at 80° C. for 5minutes. The mixture is filtered on Clarcel and the Clarcel is rinsedwith methanol. The filtrate is concentrated under reduced pressure, soas to give 250 mg of7-amino-1-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form ofa purple gum.

Method 16:7-Amino-1-methyl-6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

A mixture of 2.5 g of 5-hydroxy-1-tetralone, 30 ml of acetonitrile, 5 gof caesium carbonate and 3.87 ml of 2-iodopropane is heated for one hourat 80° C. and then evaporated to dryness. The residue is taken up inethyl acetate and water. The organic phase is washed with a saturatedsodium chloride solution, dried over magnesium sulfate, filtered andconcentrated under reduced pressure, so as to give 4.87 g of5-(propan-2-yloxy)-3,4-dihydronaphthalen-1(2H)-one in the form of anorangey-coloured oil.

A mixture of 4.39 g of5-(propan-2-yloxy)-3,4-dihydronaphthalen-1(2H)-one and 1.74 g of sodiumazide in 70 ml of TFA is refluxed for 2 hours. The reaction medium ispoured into 250 ml of water, brought to pH 7 by adding potassiumcarbonate and extracted with ethyl acetate. The organic phase is driedover magnesium sulfate, filtered and evaporated under reduced pressure.Purification is carried out by flash chromatography on silica gel (40-63μm), elution being carried out with a mixture of dichloromethane andMeOH (100/0 to 90/10). 2.87 g of6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are obtainedin the form of a beige solid.

750 mg of potassium nitrate are added, in portions, to a solution of 1.3g of 6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 13ml of trifluoroacetic anhydride brought back to −5° C. The reactionmedium is stirred for 5 minutes at −5° C. and then brought back to pH 5by adding a saturated aqueous sodium bicarbonate solution. The mixtureis extracted with ethyl acetate and the organic phase is dried overmagnesium sulfate, filtered and concentrated under reduced pressure.Purification is carried out by flash chromatography on silica gel (40-63μm), elution being carried out with a mixture of heptane and of ethylacetate (80/20 to 50/50). 450 mg of7-nitro-6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one areobtained in the form of a beige solid.

91 mg of sodium hydride at 50% are added to a solution of 445 mg of7-nitro-6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in10 ml of DMF. The reaction medium is stirred for 10 minutes at ambienttemperature and then 263 mg of iodomethane are added. The reactionmedium is stirred for 1 hour at ambient temperature, poured intoice-cold water and extracted with ethyl acetate. The organic phase isdried over magnesium sulfate, filtered and evaporated under reducedpressure, so as to give 417 mg of1-methyl-7-nitro-6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-onein the form of a yellow gum.

567 mg of ammonium formate and 478 mg of Pd/C (10%) are added to asolution of 416 mg of1-methyl-7-nitro-6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-onein 30 ml of methanol. The reaction medium is microwave-heated at 80° C.for 5 minutes. The mixture is filtered on Clarcel, and the Clarcel isrinsed with methanol. The filtrate is concentrated under reducedpressure, so as to give 380 mg of7-amino-1-methyl-6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-onein the form of a colourless gum.

Method 17: 8-Amino-1-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

5 g of alpha-tetralone are added to 18.2 ml of sulfuric acid cooled to0° C., while maintaining the temperature <10° C. A mixture of 1.87 ml ofnitric acid at 70% in water and of 3.65 ml of sulfuric acid is addedwhile maintaining the temperature <10° C. The reaction medium is stirredfor 30 minutes at a temperature <10° C. and then stirred for one hour atambient temperature. The reaction medium is poured into ice-cold water(250 ml). The insoluble material is filtered off under vacuum and dried,so as to give 5.2 g of 7-nitro-3,4-dihydronaphthalen-1(2H)-one in theform of a beige solid.

A mixture of 5 g of 7-nitro-3,4-dihydronaphthalen-1(2H)-one, 2.18 g ofhydroxylamine hydrochloride, 4.29 g of sodium acetate in 90 ml ofethanol and 90 ml of water is refluxed for one hour. The reaction mediumis brought back to ambient temperature and an aqueous 10% sodiumbicarbonate solution is added until a pH of 7 is reached. The mixture isextracted with ethyl acetate and the organic phase is dried overmagnesium sulfate, filtered and concentrated under reduced pressure.Purification is carried out by flash chromatography on silica gel (40-63μm), elution being carried out with a mixture of heptane and of ethylacetate (80/20 to 50/50). 1.14 g of(1E)-N-hydroxy-7-nitro-3,4-dihydronaphthalen-1(2H)-imine are obtained inthe form of a yellow solid.

A mixture of 1.11 g of(1E)-N-hydroxy-7-nitro-3,4-dihydronaphthalen-1(2H)-imine and 13 g ofpolyphosphoric acid is heated at 125° C. for 16 hours. The reactionmedium is poured into ice-cold water and extracted with ethyl acetate.The organic phase is washed with a saturated sodium chloride solution,dried over magnesium sulfate, filtered and concentrated under reducedpressure. 549 mg of 8-nitro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one areobtained in the form of a beige solid.

144 mg of NaH (50%) are added to a solution of 549 mg of8-nitro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 15 ml of DMF. Thereaction medium is stirred for 15 minutes and then 187 μl of iodomethaneare added. The mixture is stirred for 16 hours at ambient temperatureand then run into ice-cold water and extracted with ethyl acetate. Theorganic phase is washed with a saturated sodium chloride solution, driedover magnesium sulfate, filtered and concentrated under reducedpressure. The residue is taken up in diisopropyl ether and the insolublematerial is filtered off and dried under vacuum, so as to give 405 mg of1-methyl-8-nitro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form ofa beige solid.

696 mg of ammonium formate and 581 mg of Pd/C (10%) are added to asolution of 405 mg of1-methyl-8-nitro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 39 ml ofmethanol. The reaction medium is microwave-heated at 80° C. for 5minutes. The mixture is filtered on Clarcel, and the Clarcel is rinsedwith methanol. The filtrate is concentrated under reduced pressure, soas to give 422 mg of8-amino-1-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form ofa colourless gum.

Method 18: 2-Isopropoxy-4-(4-methylpiperazin-1-ylmethyl)phenylamine

3.0 g of 3-hydroxy-4-nitrobenzaldehyde, 30 ml of acetonitrile, 5.9 g ofcaesium carbonate and 4.1 ml of 2-iodopropane are successivelyintroduced into a three-necked round-bottomed flask under argon. Thereaction mixture is heated at 70° C. for 17 h. After cooling to ambienttemperature, the mixture is filtered through a sintered glass filter andthe filtrate is concentrated to dryness under reduced pressure. Theresidue is taken up in a mixture of 50 ml of ethyl acetate and 15 ml ofwater, and then separated by settling out. The aqueous phase isseparated and the organic phase is washed with 10 ml of water. Theorganic phase is then dried over magnesium sulfate and then concentratedto dryness under reduced pressure, so as to obtain 3.6 g of3-isopropoxy-4-nitrobenzaldehyde in the form of a dark brown liquid.

3.25 ml of 1-methylpiperazine are added to a solution of 3.06 g of3-isopropoxy-4-nitrobenzaldehyde in 15 ml of toluene and 0.34 ml ofacetic acid in a three-necked round-bottomed flask under argon. Thereaction mixture is stirred at ambient temperature for 1.5 h and then 5ml of toluene are added, followed by 4.9 g of sodiumtriacetoxyborohydride by spatula. The reaction mixture is stirred atambient temperature for 16 h, and then treated with 4.5 ml of methanoland 75 ml of a saturated sodium hydrogen carbonate solution. Afterstirring at ambient temperature for 30 min, the mixture is extractedwith 30 ml and then 2×50 ml of ethyl acetate. The organic extracts arecombined, washed with water, dried over magnesium sulfate, and thenconcentrated to dryness under reduced pressure, so as to give 4.24 g of1-(3-isopropoxy-4-nitrobenzyl)-4-methylpiperazine in the form of a beigesolid.

A mixture of 4.2 g of 1-(3-isopropoxy-4-nitrobenzyl)-4-methylpiperazineand 420 mg of 10% palladium-on-carbon in 145 ml of ethanol ishydrogenated at 25° C. under 1 bar for 3 h. The mixture is filtered onClarcel and the Clarcel is rinsed with ethanol. The filtrate isconcentrated to dryness under reduced pressure, so as to give 3.8 g of2-isopropoxy-4-(4-methylpiperazin-1-ylmethyl)phenylamine in the form ofa brown oil.

Method 19: 2-Isopropoxy-5-(4-methylpiperazin-1-yl)phenylamine

A mixture of 5.0 g of 5-bromo-2-fluoronitrobenzene, 14.8 g of caesiumcarbonate and 35.0 ml of 2-iodopropane is charged to two 20 ml microwavetubes, and irradiated at 60° C. with stirring for 1.5 h, and thenstirred at ambient temperature overnight. The mixture is poured into 400ml of water and then extracted three times with 300 ml of ethyl acetate.The organic extracts are combined and then concentrated to dryness underreduced pressure. The residue is reintroduced into a single-neckedround-bottomed flask, into which 50 ml of 2-iodopropane and 10.0 g ofcaesium carbonate are added. The reaction mixture is heated at 95° C.for 10 min, and then at 60° C. for 3 h, and it is then stirred atambient temperature overnight. The mixture is then poured into 400 ml ofwater and then extracted three times with 400 ml of ethyl acetate. Theorganic extracts are combined and then concentrated to dryness underreduced pressure, so as to obtain 5.6 g of4-bromo-1-isopropoxy-2-nitrobenzene in the form of a brown oil.

A solution of 1.0 g of 4-bromo-1-isopropoxy-2-nitrobenzene in 36 ml of1,4-dioxane is degassed with argon for 10 min, and then 0.69 g of4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), 0.70 g oftris(dibenzylideneacetone)dipalladium(0), 2.52 g of caesium carbonateand 0.86 ml of 1-methylpiperazine are successively added. Theround-bottomed flask is rinsed with 2 ml of dioxane, and the reactionmixture is then heated at 90° C. for 43 h. After returning to ambienttemperature, the mixture is diluted with 90 ml of ethyl acetate and thenextracted with 90 ml of water. The organic phase is separated, driedover magnesium sulfate and concentrated to dryness under reducedpressure. The residue is purified by chromatography on a 70 g silicacartridge, elution being carried out with a 95/5 v/v then 50/50 v/vcyclohexane/ethyl acetate mixture, and then with a 95/5 v/vdichloromethane/methanol mixture at a flow rate of 50 ml/min, so as toobtain 0.57 g of 1-(4-isopropoxy-3-nitrophenyl)-4-methylpiperazine inthe form of a brown oil.

A mixture of 0.57 g of 1-(4-isopropoxy-3-nitrophenyl)-4-methylpiperazineand 65 mg of 10% palladium-on-carbon in 200 ml of ethanol ishydrogenated at 25° C. under 1 bar for 22 h. The mixture is filtered onClarcel and the Clarcel is rinsed with methanol. The filtrate isconcentrated to dryness under reduced pressure and the residue ispurified by chromatography on a 25 g silica cartridge, elution beingcarried out with pure dichloromethane and then successively with 98/2and 95/5 v/v dichloromethane/methanol mixtures at a flow rate of 30ml/min, so as to obtain 0.32 g of2-isopropoxy-5-(4-methylpiperazin-1-yl)phenylamine in the form of abrown solid.

Method 20: (3-Isopropoxy-4-nitrophenyl)(tetrahydropyran-4-yl)amine

A mixture of 0.75 g of 5-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 0.42g of 4-aminotetrahydropyran and 0.8 g of potassium carbonate in 6 ml ofDMSO is stirred at 50° C. overnight. The mixture is diluted with 100 mlof water and extracted three times with 50 ml of ethyl acetate. Theorganic phases are combined and then dried over magnesium sulfate andconcentrated to dryness under reduced pressure. The residue is purifiedby chromatography on a 50 g silica column, elution being carried outwith a dichloromethane/methanol (95/5 v/v) mixture, so as to obtain 0.69g of (3-isopropoxy-4-nitrophenyl)(tetrahydropyran-4-yl)amine in the formof a yellow foam.

A mixture of 0.69 g of(3-isopropoxy-4-nitrophenyl)(tetrahydropyran-4-yl)amine and 0.1 g of 10%palladium-on-carbon in a mixture of 30 ml of ethanol and 10 ml ofdichloromethane is hydrogenated at 22° C. under 2 bar for 15 h. Themixture is filtered and the filtrate is concentrated to dryness underreduced pressure. The residue is purified by chromatography on a 50 gsilica column, elution being carried out with a dichloromethane/methanol(95/5 v/v) mixture, so as to obtain 0.4 g of(3-isopropoxy-4-nitrophenyl)(tetrahydropyran-4-yl)amine in the form of apurple oil.

Method 21: 2-Isopropoxy-3-(4-methylpiperazine-1-yl)phenylamine

1.23 g of potassium carbonate, 14.6 g of caesium carbonate, 22 ml ofdimethylformamide and 1.0 g of 2-bromo-6-nitrophenol are successivelyintroduced into a three-necked round-bottomed flask under argon. Theresulting suspension is stirred at ambient temperature for 10 min, andthen 0.91 ml of 2-iodopropane is added in one go. The round-bottomedflask is rinsed with 10 ml of dimethylformamide and then the reactionmixture is heated at 40° C. for 48 h. After cooling to ambienttemperature, the mixture is treated with 50 ml of water and extractedfour times with 30 ml of ethyl acetate. The organic extracts arecombined and washed with 30 ml of saturated brine and then 30 ml ofwater. The organic phase is then dried over magnesium sulfate and thenconcentrated to dryness under reduced pressure. The residue is purifiedby chromatography on a 30 g silica cartridge, elution being carried outwith a 95/5 v/v cyclohexane/ethyl acetate mixture at a flow rate of 30ml/min, so as to obtain 1.04 g of 1-bromo-2-isopropoxy-3-nitrobenzene inthe form of a yellow oil.

A solution of 1.04 g of 1-bromo-2-isopropoxy-3-nitrobenzene in 37 ml of1,4-dioxane is degassed with argon for 10 min, and then 0.72 g of4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), 0.73 g oftris(dibenzylideneacetone)dipalladium(0), 2.62 g of caesium carbonateand 0.90 ml of 1-methylpiperazine are successively added. Theround-bottomed flask is rinsed with 3 ml of dioxane, and then thereaction mixture is heated at 90° C. for 19 h. After returning toambient temperature, the mixture is diluted with 90 ml of ethyl acetateand then extracted with 90 ml of water. The organic phase is separated,dried over magnesium sulfate and concentrated to dryness under reducedpressure. The residue is purified by chromatography on a 90 g silicacartridge, elution being carried out with a 98/2 v/vdichloromethane/methanol mixture, at a flow rate of 50 ml/min, so as toobtain 0.31 g of 1-(2-isopropoxy-3-nitrophenyl)-4-methylpiperazine inthe form of a brown oil.

A mixture of 0.80 g of 1-(2-isopropoxy-3-nitrophenyl)-4-methylpiperazineand 91 mg of 10% palladium-on-carbon in 300 ml of ethanol ishydrogenated at 25° C. under 1 bar for 22 h. The mixture is filtered onClarcel and the Clarcel is rinsed with ethanol. The filtrate isconcentrated to dryness under reduced pressure and the residue ispurified by chromatography on a 50 g silica cartridge, elution beingcarried out with pure dichloromethane and then successively with 98/2and 95/5 v/v dichloromethane/methanol mixtures at a flow rate of 30ml/min, so as to obtain 0.60 g of2-isopropoxy-3-(4-methylpiperazine-1-yl)phenylamine in the form of ayellow powder.

Method 22: 2-Isopropoxy-N4-(1-methylpiperidin-4-yl)benzene-1,4-diamine

1.7 g of potassium carbonate and 1.0 g of 4-amino-1-methylpiperidine aresuccessively added to a solution of 1.6 g of4-fluoro-2-isopropoxy-1-nitrobenzene in 13.5 ml of dimethyl sulfoxide.The reaction mixture is heated at 120° C. for 3 h and is then cooled toambient temperature and poured into a mixture of 150 ml of ice-coldwater and 100 ml of ethyl acetate. After settling out, the organic phaseis separated and the aqueous phase is extracted twice with 70 ml ofethyl acetate. The organic extracts are combined, dried over magnesiumsulfate and then concentrated to dryness under reduced pressure. Theresidue is purified by chromatography on a 90 g silica cartridge,elution being carried out with a 97.5/2/0.5 v/v/vdichloromethane/methanol/20% aqueous ammonia mixture at a flow rate of50 ml/min, so as to obtain 1.5 g of(3-isopropoxy-4-nitrophenyl)(1-methylpiperidin-4-yl)amine in the form ofa bright yellow oil.

A mixture of 1.49 g of(3-isopropoxy-4-nitrophenyl)(1-methylpiperidin-4-yl)amine and 150 mg of10% palladium-on-carbon in 60 ml of ethanol is hydrogenated at 25° C.under 1 bar for 3 h. The mixture is filtered on Clarcel and the Clarcelis rinsed with ethanol. The filtrate is concentrated to dryness underreduced pressure and the residue is purified by chromatography on a 70 gsilica cartridge, elution being carried out with a 96.5/3/0.5 v/v/vdichloromethane/methanol/28% aqueous ammonia mixture at a flow rate of50 ml/min, so as to obtain 0.9 g of2-isopropoxy-N4-(1-methylpiperidin-4-yl)benzene-1,4-diamine in the formof a brown liquid.

Method 23: 2-Methylpropan-2-yl7-[4-amino-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane-1-carboxylate

A mixture of 3.0 g of tert-butyl 1,7-diazaspiro[4.4]nonane-1-carboxylateand 2.64 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene (obtainedaccording to method 6), and 2.75 g of potassium carbonate in DMSO isstirred at ambient temperature overnight. The mixture is taken up withethyl acetate and washed twice with 10 volumes of water. The organicphase is dried over magnesium sulfate and concentrated under vacuum. Thecrude product is purified on 120 g of silica, elution being carried outwith dichloromethane, so as to obtain 3.40 g of 2-methylpropan-2-yl7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane-1-carboxylatein the form of a dark yellow solid.

A mixture of 400 mg of 2-methylpropan-2-yl7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane-1-carboxylate,592 mg of hydrazine hydrate and 52.5 mg of 10% palladium-on-carbon in 10ml of ethanol is refluxed for 1 h. The mixture is filtered and thefiltrate is concentrated under reduced pressure, so as to obtain 365 mgof 2-methylpropan-2-yl7-[4-amino-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane-1-carboxylatein the form of a mauve gum.

Method 24:4-(1-Methyl-1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)aniline

A mixture of 1.42 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 1.0 gof 1-methyl-1,7-diazaspiro[4,4]nonane and 1.48 g of potassium carbonatein 10 ml of DMSO is stirred at ambient temperature overnight. Themixture is diluted with 160 ml of water and extracted three times with100 ml of ethyl acetate. The organic phases are dried over magnesiumsulfate and concentrated under vacuum. The yellow oily residue ispurified on silica, with an elution gradient withdichloromethane/methanol (100/0 then 90/10), so as to obtain 160 mg of1-methyl-7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonanein the form of an orangey-coloured oil.

A mixture of 160 mg of1-methyl-7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane,301 mg of hydrazine hydrate and 27 mg of 10% palladium-on-carbon in 30ml of ethanol is heated at 80° C. (bath) for 2 h. The mixture isfiltered and the filtrate is concentrated under vacuum, so as to obtain141 mg of4-(1-methyl-1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)aniline inthe form of a brown oil.

Method 25:4-(1-Ethyl-1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)aniline

0.33 ml of trifluoroacetic acid is added to a solution of 300 mg of2-methylpropan-2-yl7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane-1-carboxylatein 30 ml of dichloromethane. The mixture is stirred at ambienttemperature for 15 hours and then 3 ml of trifluoroacetic acid are againadded. After stirring for 15 hours, the reaction mixture is run into 50ml of a saturated potassium carbonate solution. The aqueous phase isextracted three times with 50 ml of dichloromethane. The organic phasesare combined, dried over anhydrous magnesium sulfate, filtered and thenconcentrated to dryness under reduced pressure, so as to give a yellowoil. The residue is purified by chromatography on silica gel, elutionbeing carried out with dichloromethane/methanol (100/0 to 95/5), so asto obtain 221 mg of7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane in theform of a yellow solid.

1.0 ml of acetaldehyde is added to a solution of 500 mg of7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane in 20 mlof 1,4-dichloroethane, cooled in a bath of ice-cold water. After 30minutes, 1.12 g of sodium triacetoxyborohydride are added in smallportions and the mixture is left to return to ambient temperature. Themixture is stirred at ambient temperature for 15 hours. 1 ml ofacetaldehyde is then added and the mixture is stirred for 7 h. Themixture is concentrated to dryness under reduced pressure and theresidue is diluted in 100 ml of dichloromethane. The organic phase iswashed three times with 50 ml of water and the organic phase is driedover anhydrous magnesium sulfate, filtered and then concentrated todryness under reduced pressure. The residue is purified bychromatography on silica gel, elution being carried out with adichloromethane/isopropanol gradient: 100/0 to 50/50, and then byfurther chromatography on silica gel, elution being carried out with adichloromethane/acetone gradient: 100/0 to 50/50, so as to obtain ayellow oil. This oil is taken up with ether, and the precipitateobtained is filtered off. The filtrate is concentrated to dryness underreduced pressure, so as to give 250 mg of1-ethyl-7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonanein the form of a yellow oil.

A mixture of 250 mg of1-ethyl-7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane,450 mg of hydrazine hydrate and 40 mg of 10% palladium-on-carbon in 10ml of ethanol is heated at 80° C. (bath) for 4 h 30 min. 450 mg ofhydrazine hydrate are then added and the reflux is maintained for 1 h.The mixture is filtered and the filtrate is concentrated under vacuum,so as to obtain 230 mg of4-(1-ethyl-1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)aniline in theform of a brown oil.

Method 26:4-[(8aR)-Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(propan-2-yloxy)aniline

A mixture of 1.0 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 634 mgof (R)-1,4-diazabicyclo[4,3,0]nonane and 1.04 g of potassium carbonatein 7 ml of DMSO is stirred at ambient temperature for 21 hours. Thereaction medium is run into 15 ml of water and the mixture is thenextracted three times with 30 ml of ethyl acetate. The organic phasesare dried over magnesium sulfate, filtered and concentrated undervacuum, so as to obtain 1.44 g of(8aR)-2-[4-nitro-3-(propan-2-yloxy)phenyl]octahydropyrrolo[1,2-a]pyrazinein the form of an orangey-coloured oily residue.

A mixture of 1.38 g of(8aR)-2-[4-nitro-3-(propan-2-yloxy)phenyl]octahydropyrrolo[1,2-a]pyrazine,2.72 g of hydrazine hydrate and 240 mg of 10% palladium-on-carbon (240mg, 5 mol %) in 30 ml of ethanol is heated at 80° C. (bath) for 1 h 30.The mixture is filtered on Clarcel and the filtrate is concentratedunder vacuum, so as to obtain 1.23 g of4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(propan-2-yloxy)anilinein the form of a purple oil.

Method 27: 2-{4-[4-Amino-3-(propan-2-yloxy)phenyl]piperidin-1-yl}ethanol

A mixture of 100 mg of 4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridine (seemethod 1) and 0.075 ml of 2-iodoethanol in 1.7 ml of acetonitrile isheated at 85° C. (bath) for 1 h. 75 μl of 2-iodoethanol are then addedand the heating is continued for 15 h at 91° C. The mixture is thenconcentrated under vacuum, so as to obtain a solid which is taken upwith 10 ml of ethyl ether. The resulting heterogeneous mixture isfiltered and the solid is rinsed with ethyl ether and dried underreduced pressure, so as to obtain 147 mg of1-(2-hydroxyethyl)-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodidein the form of a solid.

44 g of sodium borohydride are added, at a temperature of about 0° C.(ice/water bath) to a solution of 0.142 g of1-(2-hydroxyethyl)-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodidein 2.6 ml of methanol. After 30 minutes, a few drops of water are addedand the mixture is left to return to ambient temperature. The mixture isconcentrated to dryness under reduced pressure and then diluted with 150ml of ethyl acetate. The organic phase is washed successively with 120ml of a saturated sodium hydrogen carbonate solution and then 70 ml of asaturated sodium chloride solution. The organic phase is dried overanhydrous magnesium sulfate, filtered and then concentrated to drynessunder reduced pressure, so as to obtain 90 mg of2-{4-[4-nitro-3-(propan-2-yloxy)phenyl]-3,6-dihydropyridin-1(2H)-yl}ethanol.

A mixture of 150 mg of 10% palladium-on-carbon and 400 mg of2-{4-[4-nitro-3-(propan-2-yloxy)phenyl]-3,6-dihydropyridin-1(2H)-yl}ethanolin 15 ml of ethanol is heated at 80° C. with stirring. 1.25 g ofammonium formate are then added in two portions. After stirring at 80°C. for 1 h. the mixture is allowed to return to ambient temperature andis filtered on Clarcel. The Clarcel is rinsed with 200 ml of ethanol andthe filtrate is concentrated under vacuum, so as to obtain a residuewhich is solubilised in 150 ml of dichloromethane. The organic phase iswashed three times with 70 ml of a saturated potassium carbonatesolution, and the aqueous phase is extracted twice with 100 ml ofdichloromethane. The combined organic phases are dried over magnesiumsulfate, filtered and concentrated under vacuum, so as to obtain 330 mgof 2-{4-[4-amino-3-(propan-2-yloxy)phenyl]piperidin-1-yl}ethanol usedwithout further purification.

Method 28:(3R)-1-[4-Amino-3-(propan-2-yloxy)phenyl]-N-methyl-N-(oxetan-3-yl)piperidin-3-amine

A mixture of 3.0 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 5.0 gof (R)-3-Boc-aminopiperidine and 3.12 g of potassium carbonate in 28 mlof DMSO is stirred at ambient temperature overnight. The mixture isdiluted with 30 ml of water and extracted three times with 60 ml ofethyl acetate. The organic phases are dried over magnesium sulfate andconcentrated under vacuum. The residue is purified by flashchromatography on silica gel, using a dichloromethane/ethyl acetate(98/2 to 90/10) elution gradient, so as to obtain 5.71 g of2-methylpropan-2-yl{(3R)-1-[4-nitro-3-(propan-2-yloxy)phenyl]piperidin-3-yl}carbamate inthe form of a yellow solid.

6.25 ml of trifluoroacetic acid are added, at a temperature of about 20°C., to 5.32 g of 2-methylpropan-2-yl{(3R)-1-[4-nitro-3-(propan-2-yloxy)phenyl]piperidin-3-yl}carbamate insolution in 106 ml of dichloromethane, and the mixture is left to stirfor 15 h. A further 2 ml of trifluoroacetic acid are added and thestirring is continued for 1 h. The mixture is concentrated under reducedpressure, so as to obtain an oily residue which is precipitated byadding ethyl ether. The solid obtained is filtered off and then washedwith ethyl ether, so as to obtain 5.42 g of(3R)-1-[4-nitro-3-(propan-2-yloxy)phenyl]piperidin-3-aminetrifluoroacetate in the form of a yellow solid.

5.11 g of (3R)-1-[4-nitro-3-(propan-2-yloxy)phenyl]piperidin-3-aminetrifluoroacetate are added to 40 ml of a saturated potassium carbonatesolution and then the mixture is extracted three times with 50 ml ofdichloromethane. The combined organic phases are dried over magnesiumsulfate, filtered and concentrated under vacuum so as to give 3.60 g of(3R)-1-[4-nitro-3-(propan-2-yloxy)phenyl]piperidin-3-amine in the formof a yellow solid.

2 ml of 3-oxetanone are added, at a temperature of about 20° C., to asolution of 1.50 g of(3R)-1-[4-nitro-3-(propan-2-yloxy)phenyl]piperidin-3-amine in 54 ml of1,4-dichloroethane, under an argon atmosphere. After stirring of themixture, 3.69 g of sodium triacetoxyborohydride are added in smallportions and the reaction mixture is heated at 70° C. for 3 h. Afterreturning to ambient temperature, 70 ml of a dilute sodium hydrogencarbonate solution are added. The aqueous phase is extracted twice with80 ml of dichloromethane. The combined organic phases are dried overmagnesium sulfate, filtered and concentrated under vacuum, so as toobtain an orangey-coloured oily residue. The residue is purified bychromatography on silica gel, using a dichloromethane/isopropanol (98/2to 94/6) elution gradient, so as to obtain 1.2 g of(3R)-1-[4-nitro-3-(propan-2-yloxy)phenyl]-N-(oxetan-3-yl)piperidin-3-aminein the form of an orangey-coloured gum.

65 μl of iodomethane are added, at a temperature of about 20° C., underan argon atmosphere and with magnetic stirring, to a mixture of 293 mgof(3R)-1-[4-nitro-3-(propan-2-yloxy)phenyl]-N-(oxetan-3-yl)piperidin-3-amineand 427 mg of caesium carbonate in 8 ml of anhydrous DMF. After stirringfor 3 hours, 100 μl of iodomethane are added and the mixture is left tostir for a further 2 h. 10 ml of water are then added and the mixture isthen extracted three times with 15 ml of ethyl acetate. The combinedorganic phases are dried over magnesium sulfate, filtered andconcentrated under vacuum so as to give an oily yellow residue. Theresidue is purified by flash chromatography on silica gel, using adichloromethane/methanol (98/2) eluent, so as to obtain 47 mg of(3R)—N-methyl-1-[4-nitro-3-(propan-2-yloxy)phenyl]-N-(oxetan-3-yl)piperidin-3-aminein the form of an orangey-yellow solid.

24 mg of palladium-on-carbon (10%) and then 0.269 ml of hydrazinehydrate are added to a solution of 161 mg of(3R)—N-methyl-1-[4-nitro-3-(propan-2-yloxy)phenyl]-N-(oxetan-3-yl)piperidin-3-aminein 4 ml of ethanol. This mixture is heated at between 85° C./90° C. withmagnetic stirring for 1 h 30, then 24 mg of palladium-on-carbon (10%)are added while continuing the refluxing for 2 h. 24 mg ofpalladium-on-carbon (10%) and 0.269 ml of hydrazine hydrate are againadded. The mixture is heated for 1 h at 85° C./90° C., and then allowedto return to ambient temperature and the mixture is filtered through aWhatman AutoCup sintered glass funnel. The filtrate is concentratedunder vacuum so as to obtain 136 mg of(3R)-1-[4-amino-3-(propan-2-yloxy)phenyl]-N-methyl-N-(oxetan-3-yl)piperidin-3-aminein the form of an orangey-yellow solid which is used for the subsequentstep without further purification.

Rf=0.61 (TLC, silica support), eluent dichloromethane/MeOH (95/5), UV254 nm.

Method 29: 2-Methylpropan-2-yl4-[5-amino-1-(propan-2-yl)-1H-pyrazol-3-yl]piperidine-1-carboxylate

1.82 ml of triethylamine are added to a solution of 3.18 g of4-(2-cyanoacetyl)piperidine-1-carboxylic acid tert-butyl ester and 1.41g of isopropylhydrazine hydrochloride in 70 ml of ethanol under an argonatmosphere. The mixture is refluxed with magnetic stirring for 3 hours,and then concentrated to dryness under reduced pressure. The residue istaken up in a mixture of 100 ml of water and 100 ml of ethyl acetate,and then the organic phase is washed twice with 100 ml of water. Thecombined aqueous phases are extracted twice with 100 ml of ethylacetate. The combined organic phases are dried over magnesium sulfate,filtered and concentrated under reduced pressure, so as to obtain 3.9 gof 2-methylpropan-2-yl4-[5-amino-1-(propan-2-yl)-1H-pyrazol-3-yl]piperidine-1-carboxylate inthe form of a solid.

Method 30:1-(Propan-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine

26.8 ml of a 1M solution of LiHMDS in THF are introduced into 25 ml ofanhydrous THF under an argon atmosphere. The mixture is maintained at atemperature of about −78° C., and then 1.47 ml of acetonitrile insolution in 3 ml of anhydrous THF are added. The reaction mixture iskept stirring at −78° C. for 40 minutes and then a solution of 3.0 g ofmethyl tetrahydropyran-4-carboxylate in 3 ml of THF is added. Afterstirring for 2 hours at −78° C., the mixture is left to return toambient temperature for 15 hours and it is then diluted with 200 ml of awater/ice mixture. The pH is adjusted to a value of about 3 by adding 2NHCl, and then the mixture is extracted three times with 150 ml of ethylacetate. The combined organic phases are dried over anhydrous magnesiumsulfate, filtered and then concentrated to dryness under reducedpressure, so as to give 3.18 g of3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile in the form of a lightbrown oil.

0.43 ml of triethylamine is added to a solution of 640 mg of3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile and 347 mg ofisopropylhydrazine hydrochloride in 8 ml of ethanol under an argonatmosphere. The mixture is refluxed with magnetic stirring for 1 h andthen concentrated to dryness under reduced pressure. The residue istaken up in 100 ml of ethyl acetate and the organic phase is washedtwice with 40 ml of a saturated sodium hydrogen carbonate solution. Thecombined aqueous phases are extracted twice with 50 ml of ethyl acetate.The combined organic phases are dried over magnesium sulfate, filteredand concentrated under reduced pressure, so as to obtain 536 mg of1-(propan-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine.

Method 31: 4-Methoxy-2-(propan-2-yloxy)aniline

A mixture of 5.0 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 4.07 gof sodium methoxide and 200 mg of 18C6 in 100 ml of methanol is heatedat 65° C. for 2 h. The mixture is then concentrated and the residue istaken up with a mixture of water and ethyl acetate. The aqueous phase isextracted three times with ethyl acetate. The combined organic phasesare dried over anhydrous magnesium sulfate, filtered and thenconcentrated to dryness under reduced pressure, so as to obtain 5.0 g of1-nitro-4-methoxy-2-(propan-2-yloxy)benzene.

A solution of 5.0 g of 1-nitro-4-methoxy-2-(propan-2-yloxy)benzene in300 ml of methanol is hydrogenated on 2.5 g of platinum oxide at ahydrogen pressure of 15 bar, for 2 h at ambient temperature. The mixtureis filtered and the filtrate is concentrated to dryness under reducedpressure, so as to obtain 4.36 g of 4-methoxy-2-(propan-2-yloxy)aniline.

Method 32: 4-Chloro-2-(propan-2-yloxy)aniline

A mixture of 1.0 g of 4-chloro-2-fluoronitrobenzene and 9.3 g of caesiumcarbonate in 10 ml of 2-propanol is heated at 60° C. for 24 h. Themixture is then concentrated and the residue is taken up with 100 ml ofa mixture of water and ethyl acetate. The aqueous phase is extractedthree times with 50 ml of ethyl acetate. The combined organic phases arewashed with 50 ml of a saturated sodium chloride solution, dried overanhydrous magnesium sulfate, filtered and then concentrated to drynessunder reduced pressure. The residue is purified on 90 g of silica,elution being carried out with 95/5 heptane/ethyl acetate, so as toobtain 885 mg of 4-chloro-1-nitro-2-(propan-2-yloxy)benzene in the formof a yellow solid.

A mixture of 2.55 g of 4-chloro-1-nitro-2-(propan-2-yloxy)benzene in 40ml of acetic acid is heated at 50° C., and then 7 ml of water and 2.64 gof iron powder are added. The mixture is stirred for 1 h at 50° C., andthen cooled to ambient temperature and filtered on Celite. The Celite isrinsed three times with 20 ml of methanol, and the filtrate isconcentrated under reduced pressure. The residue is taken up in 50 ml of1N sodium hydroxide and 50 ml of dichloromethane. The aqueous phase isextracted twice with 50 ml of dichloromethane. The combined organicphases are dried over anhydrous magnesium sulfate, filtered and thenconcentrated to dryness under reduced pressure, so as to obtain 2.25 gof 4-chloro-2-(propan-2-yloxy)aniline in the form of a green oil.

Method 33: 4-(4-Methyl-1,4-diazepan-1-yl)-2-(propan-2-yloxy)aniline

A mixture of 250 mg of 4-bromo-1-nitro-2-(propan-2-yloxy)benzene, 1.13 gof caesium carbonate, 197 mg of N-methylhomopiperazine, 47.5 mg oftris(dibenzylideneacetone)dipalladium(0) and 50 mg of9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene in 5 ml of 1,4-dioxaneis microwave-heated in a sealed tube, at 150° C. for 30 min, and then200° C. for 10 min. The mixture is diluted with ethyl acetate andfiltered on Clarcel. The Clarcel is washed with ethyl acetate and theorganic phase is washed with water. The organic phase is dried overanhydrous magnesium sulfate, filtered and then concentrated to drynessunder reduced pressure. The residue is purified on 12 g of silica,elution being carried out with 0-5% methanol in dichloromethane, so asto obtain 110 mg of4-(4-methyl-1,4-diazepan-1-yl)-2-(propan-2-yloxy)nitrobenzene in theform of an orangey-coloured oil.

A solution of 267 mg of4-(4-methyl-1,4-diazepan-1-yl)-2-(propan-2-yloxy)nitrobenzene in 90 mlof methanol is hydrogenated using an H-cube, on a cartridge of 10%palladium-on-carbon, at a flow rate of 1 ml/min. The hydrogenatedsolution is concentrated under reduced pressure, so as to obtain 220 mgof 4-(4-methyl-1,4-diazepan-1-yl)-2-(propan-2-yloxy)aniline in the formof a grey oil.

Method 34:7-Amino-1-methyl-8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

A suspension of 2.0 g of 7-hydroxy-3,4-dihydronaphthalen-1(2H)-one, 4.04g of caesium carbonate and 3.15 ml of 2-iodopropane in 23 ml ofacetonitrile is heated for 1 hour at 80° C. The reaction medium isbrought back to ambient temperature and then evaporated to dryness. Theresidue is taken up with 100 ml of water and 100 ml of ethyl acetate.The organic phase is dried over magnesium sulfate, filtered andevaporated under reduced pressure, so as to obtain 2.24 g of7-(propan-2-yloxy)-3,4-dihydronaphthalen-1(2H)-one in the form of anorangey-coloured oil.

900 mg of sodium azide are added at ambient temperature to a solution of2.24 g of 7-(propan-2-yloxy)-3,4-dihydronaphthalen-1(2H)-one in 35 ml oftrifluoroacetic acid. The reaction medium is refluxed for 3 hours and isthen brought back to ambient temperature. The reaction medium is pouredinto 100 ml of water and the pH is adjusted to pH 7 by adding sodiumcarbonate. The mixture is extracted twice with 100 ml of ethyl acetate.The combined organic phases are dried over magnesium sulfate, filteredand evaporated. The residue is purified by flash chromatography onsilica gel, elution being carried out with dichloromethane and then adichloromethane/methanol (9/1) mixture, so as to obtain 346 mg of8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the formof an orangey-coloured oil.

460 mg of potassium nitrate are added to a solution of 797 mg of8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 8 ml oftrifluoroacetic anhydride, cooled to −5° C. The reaction medium isstirred for 5 minutes at −5° C., brought back to pH 7 by adding asaturated aqueous sodium hydrogen carbonate solution, and then extractedwith 100 ml of ethyl acetate. The organic phase is dried over magnesiumsulfate, filtered and evaporated. The residue is purified by flashchromatography on silica gel, elution being carried out with aheptane/ethyl acetate (1/1) mixture, so as to obtain 489 mg of7-nitro-8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one inthe form of a yellow solid.

100 mg of sodium hydride at 60% are added to a solution of 485 mg of7-nitro-8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 8ml of DMF, cooled to 0° C. The reaction medium is stirred for 5 minutesand then 263 mg of iodomethane are added. The reaction medium is broughtback to ambient temperature and stirred for 1 hour at this temperature.The reaction medium is poured into 100 ml of ice-cold water and themixture is extracted with 100 ml of ethyl acetate. The organic phase isdried over magnesium sulfate, filtered and evaporated. The residue ispurified by flash chromatography on silica gel, elution being carriedout with a heptane/ethyl acetate (1/1) mixture, so as to obtain 318 mgof1-methyl-7-nitro-8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-onein the form of a yellow solid.

In a microwave tube, 316 mg of1-methyl-7-nitro-8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-oneare introduced into 20 ml of methanol. 443 mg of ammonium formate and363 mg of Pd/C (10%) are added. The reaction medium is microwave-heatedat 80° C. for 5 minutes. The mixture is filtered on Clarcel and theClarcel is rinsed with methanol. The filtrate is concentrated underreduced pressure, so as to obtain 280 mg of7-amino-1-methyl-8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-onein the form of a colourless gum.

Method 35:4-(1,2,2,6,6-Pentamethylpiperidin-4-yl)-2-(propan-2-yloxy)aniline

180 μl of formaldehyde and 3.4 ml of formic acid are added to a solutionof 500 mg of2,2,6,6-tetramethyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]-1,2,3,6-tetrahydropyridine(obtained according to method 2) in 15 ml of DMSO. The tube ismicrowave-heated at 100° C. for 5 minutes. After cooling, the mixture isrun into water and extracted with ethyl acetate. The organic phase iswashed with a saturated sodium chloride solution, dried over magnesiumsulfate, filtered and concentrated under reduced pressure. Purificationis carried out by flash chromatography on silica gel, elution beingcarried out with a mixture of dichloromethane and methanol (95/5), so asto obtain 230 mg of1,2,2,6,6-pentamethyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]-1,2,3,6-tetrahydropyridinein the form of a yellow oil.

In a microwave tube, 230 mg of1,2,2,6,6-pentamethyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]-1,2,3,6-tetrahydropyridineare introduced into 11.5 ml of methanol. 262 mg of ammonium formate and221 mg of Pd/C (10%) are added. The reaction medium is microwave-heatedat 80° C. for 5 minutes. The mixture is filtered on Clarcel and theClarcel is rinsed with methanol. The filtrate is concentrated underreduced pressure and the residue is purified by flash chromatography onalumina, elution being carried out with a dichloromethane/methanol(98/2) mixture, so as to obtain 120 mg of4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2-(propan-2-yloxy)aniline in theform of a yellow oil.

Method 36: 4-(1-Methyl-1H-pyrazol-3-yl)-2-(propan-2-yloxy)aniline

1.02 g of 3-iodo-1-methyl-1H-pyrazole are introduced into 33 ml of1-4-dioxane. After sparging with argon for 10 min in the reactionmedium, 1.5 g of4,4,5,5-tetramethyl-2-[4-nitro-3-(propan-2-yloxy)phenyl]-1,3,2-dioxaborolane(obtained as in method 2), 4.77 g of caesium carbonate, 6.5 ml of waterand 179 mg of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(I)are added. The reaction medium is heated for 1 hour at 90° C. and isthen diluted with ethyl acetate and water. The aqueous phase isextracted twice with ethyl acetate. The combined organic phases aredried over magnesium sulfate and concentrated under vacuum. The residueis purified by flash chromatography on silica gel, elution being carriedout with dichloromethane and then a dichloromethane/methanol (98/2)mixture, so as to give 865 mg of1-methyl-3-[4-nitro-3-(propan-2-yloxy)phenyl]-1H-pyrazole in the form ofan orange oil.

In a microwave tube, 860 mg of1-methyl-3-[4-nitro-3-(propan-2-yloxy)phenyl]-1H-pyrazole are introducedinto 30 ml of methanol. 1.25 g of ammonium formate and 1.05 g of Pd/C(10%) are added. The reaction medium is microwave-heated at 80° C. for 3times 7 minutes. The mixture is filtered on Clarcel and the Clarcel isrinsed with methanol. The filtrate is concentrated under reducedpressure and the residue is taken up with 30 ml of ethyl acetate and 3ml of water. The organic phase is dried over magnesium sulfate, filteredand concentrated under reduced pressure. The residue is purified byflash chromatography on silica gel, elution being carried out with adichloromethane/methanol (95/5) mixture, so as to obtain 110 mg of4-(1-methyl-1H-pyrazol-3-yl)-2-(propan-2-yloxy)aniline in the form of apurple oil.

The compounds (IIIa) obtained according to Example 8 (methods 1 to 36)are described in Table 2.

TABLE 2 Compounds IIIa Name Method IIIa-12-Methoxy-4-[1-(propan-2-yl)piperidin-4-yl]aniline WO2009/020990 p92IIIa-2 2-Methoxy-5-methyl-4-(1-methylpiperidin-4-yl)aniline Analogy withWO2008/073687 p48 IIIa-34-(1-Methylpiperidin-4-yl)-2-(propan-2-yloxy)aniline Method 1 IIIa-42-Methylpropan-2-yl 4-[4-amino-3-(propan-2- Method 5yloxy)phenyl]piperidine-1-carboxylate IIIa-52-(Propan-2-yloxy)-4-[1-(propan-2-yl)piperidin-4- Method 1 yl]anilineIIIa-6 4-(1-Cyclopropylpiperidin-4-yl)-2-(propan-2- Method 2yloxy)aniline IIIa-7 5-Methyl-4-(1-methylpiperidin-4-yl)-2-(propan-2-WO2008/073687 p48 yloxy)aniline IIIa-84-(5-Methoxy-1-methyl-1,2,3,6-tetrahydropyridin-4- Method 3yl)-2-(propan-2-yloxy)aniline IIIa-92-(Propan-2-yloxy)-4-(2,2,6,6-tetramethylpiperidin-4- Method 2yl)aniline IIIa-10 4-(1,2,2,6,6-Pentamethylpiperidin-4-yl)-2-(propan-2-Method 35 yloxy)aniline IIIa-11 2-Methylpropan-2-yl4-[4-amino-3-(propan-2- Method 2yloxy)phenyl]-2,6-dimethylpiperidine-1-carboxylate IIIa-122-Methylpropan-2-yl 2-ethyl-4-[4-(formylamino)-3- Method 2(propan-2-yloxy)phenyl]piperidine-1-carboxylate IIIa-134-[2-Ethyl-1-methylpiperidin-4-yl]-2-(propan-2- Method 35 yloxy)anilineIIIa-14 (cis)-4-[4-Amino-3-(propan-2-yloxy)phenyl]-1- Method 4methylpiperidin-3-ol IIIa-15 2-Methylpropan-2-yl4-[4-(formylamino)-3-(propan- Method 22-yloxy)phenyl]-2-(propan-2-yl)piperidine-1- carboxylate IIIa-162-{4-[4-Amino-3-(propan-2-yloxy)phenyl]piperidin-1- Method 27 yl}ethanolIIIa-17 5-Fluoro-4-(1-methylpiperidin-4-yl)-2-(propan-2- Method 1yloxy)aniline IIIa-182-Methoxy-5-methyl-4-(1-methylpiperidin-3-yl)aniline Method 1 IIIa-194-(1-Ethylpiperidin-3-yl)-2-(propan-2-yloxy)aniline Method 1 IIIa-204-(Octahydroindolizin-8-yl)-2-(propan-2-yloxy)aniline Method 2 IIIa-212-Methoxy-4-[4-(pyrrolidin-1-yl)piperidin-1-yl]aniline US2006/46990 p6IIIa-22 2-Methyl-4-[4-(pyrrolidin-1-yl)piperidin-1-yl]aniline Method 6IIIa-23 2-Methoxy-4-[4-(propan-2-yl)piperazin-1-yl]aniline WO2009/020990p102 IIIa-24 2-Methoxy-4-(4-methylpiperazin-1-yl)aniline WO2004/080980p138 IIIa-25 4-(4-Methylpiperazin-1-yl)-2-(propan-2-yloxy)aniline Method6 IIIa-26 5-Methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2- Method 10yloxy)aniline IIIa-27 4-(3,5-Dimethylpiperazin-1-yl)-2-(propan-2- Method6 yloxy)aniline IIIa-282-(Propan-2-yloxy)-4-(3,4,5-trimethylpiperazin-1- Method 35 yl)anilineIIIa-29 4-(5,6-Dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2- Method 6(propan-2-yloxy)aniline IIIa-302-{4-[4-Amino-3-(propan-2-yloxy)phenyl]-1- Method 6methylpiperazin-2-yl}ethanol IIIa-314-[3-(2-Methoxyethyl)-4-methylpiperazin-1-yl]-2- Method 9(propan-2-yloxy)aniline IIIa-324-(4-Methyl-1,4-diazepan-1-yl)-2-(propan-2- Method 33 yloxy)anilineIIIa-33 4-[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2- Method 6yl]-2-(propan-2-yloxy)aniline IIIa-341-[4-Amino-3-(propan-2-yloxy)phenyl]-N,N- Method 6dimethylpyrrolidin-3-amine IIIa-351-[4-Amino-2-methyl-5-(propan-2-yloxy)phenyl]-N,N- Method 7dimethylpyrrolidin-3-amine IIIa-361-[4-Amino-3-(propan-2-yloxy)phenyl]-N,N- Method 6diethylpyrrolidin-3-amine IIIa-374-(1H-Imidazol-1-yl)-2-(propan-2-yloxy)aniline Method 6 IIIa-384-(2-Methyl-1H-imidazol-1-yl)-2-(propan-2- Method 6 yloxy)anilineIIIa-39 5-Methyl-4-(2-methyl-1H-imidazol-1-yl)-2-(propan-2- Method 8yloxy)aniline IIIa-40 4-(4-Methyl-1H-imidazol-1-yl)-2-(propan-2- Method6 yloxy)aniline IIIa-41 4-(2,4-Dimethyl-1H-imidazol-1-yl)-2-(propan-2-Method 6 yloxy)aniline IIIa-422-(Propan-2-yloxy)-4-(1H-1,2,4-triazol-1-yl)aniline Method 8 IIIa-43N~4~-methyl-2-(propan-2-yloxy)-N~4~-[2- Method 6(pyrrolidin-1-yl)ethyl]benzene-1,4-diamine IIIa-444-[(8aR)-Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]- Method 262-(propan-2-yloxy)aniline IIIa-45 2-Methylpropan-2-yl7-[4-amino-3-(propan-2- Method 23yloxy)phenyl]-1,7-diazaspiro[4.4]nonane-1- carboxylate IIIa-464-(1-Ethyl-1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2- Method 25yloxy)aniline IIIa-47 (3R)-1-[4-Amino-3-(propan-2-yloxy)phenyl]-N-Method 28 methyl-N-(oxetan-3-yl)piperidin-3-amine IIIa-484-(3-Methoxypyridin-4-yl)-2-(propan-2-yloxy)aniline Method 3 IIIa-494-(1-Methyl-1H-pyrazol-4-yl)-2-(propan-2- Method 36 yloxy)anilineIIIa-50 4-(1-Methyl-1H-pyrazol-3-yl)-2-(propan-2- Method 36yloxy)aniline IIIa-51 4-Methoxy-2-(propan-2-yloxy)aniline Method 31IIIa-52 8-Amino-1-methyl-1,3,4,5-tetrahydro-2H-1- Method 17benzazepin-2-one IIIa-53 7-Amino-1-methyl-1,3,4,5-tetrahydro-2H-1-Method 15 benzazepin-2-one IIIa-546-(4-Methylpiperazin-1-yl)-4-(propan-2-yloxy)pyridin- Method 12 3-amineIIIa-55 6-(1-Methylpiperidin-4-yl)-4-(propan-2-yloxy)pyridin- Method 113-amine IIIa-56 6-(4-Methylpiperazin-1-yl)-2-(propan-2-yloxy)pyridin-Method 14 3-amine IIIa-576-(1-Methylpiperidin-4-yl)-2-(propan-2-yloxy)pyridin- Method 13 3-amineIIIa-58 2-Methylpropan-2-yl 4-[5-amino-1-(propan-2-yl)-1H- Method 29pyrazol-3-yl]piperidine-1-carboxylate IIIa-59 2-Methylpropan-2-yl3-[5-(formylamino)-1-(propan- Method 292-yl)-1H-pyrazol-3-yl]piperidine-1-carboxylate IIIa-601-Phenyl-1H-pyrazol-5-amine [827-85-7] IIIa-613-Cyclopropyl-1-phenyl-1H-pyrazol-5-amine [175137-45-8] IIIa-621-(Propan-2-yl)-3-(pyridin-3-yl)-1H-pyrazol-5-amine Method 29 IIIa-633-Cyclopropyl-1-(propan-2-yl)-1H-pyrazol-5-amine Method 29 IIIa-643-Methyl-1-(propan-2-yl)-1H-pyrazol-5-amine [1124-16-9] IIIa-657-Amino-1-methyl-6-(propan-2-yloxy)-1,3,4,5- Method 16tetrahydro-2H-1-benzazepin-2-one IIIa-664-[(4-Methylpiperazin-1-yl)methyl]-2-(propan-2- Method 18 yloxy)anilineIIIa-67 4-(3,5-Dimethyl-1H-1,2.4-triazol-1-yl)-2-(propan-2- Method 8yloxy)aniline IIIa-685-(4-Methylpiperazin-1-yl)-2-(propan-2-yloxy)aniline Method 19 IIIa-692-(Propan-2-yloxy)-N~4~-(tetrahydro-2H-pyran-4- Method 20yl)benzene-1,4-diamine IIIa-701-[4-Amino-3-(propan-2-yloxy)phenyl]piperidin-4-yl Method 7 acetateIIIa-71 4-(1-Methylpyrrolidin-3-yl)-2-(propan-2-yloxy)aniline Method 2IIIa-72 1-(Propan-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-1H- Method 30pyrazol-5-amine IIIa-73 N~4~-(1-Methylpiperidin-4-yl)-2-(propan-2-Method 22 yloxy)benzene-1,4-diamine IIIa-74 2-Methylpropan-2-yl4-(5-amino-1-cyclobutyl-1H- Method 29pyrazol-3-yl)piperidine-1-carboxylate IIIa-753-(4-Methylpiperazin-1-yl)-2-(propan-2-yloxy)aniline Method 21 IIIa-765-Methyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-7- Analogy with amineUS20100173823 p36 IIIa-774-(4-Ethylpiperazin-1-yl)-2-(propan-2-yloxy)aniline Method 6 IIIa-787-Amino-1-methyl-8-(propan-2-yloxy)-1,3,4,5- Method 34tetrahydro-2H-1-benzazepin-2-one IIIa-794-Chloro-2-(propan-2-yloxy)aniline Method 32 IIIa-804-(1-Methyl-1,7-diazaspiro[4.4]non-7-yl)-2-(propan- Method 62-yloxy)aniline

IV—Formation of the Compounds of Formula (IIIb) (Example 9) Example 9.1:N-[4-(1-Methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]formamide

A solution of 12.3 g of acetic anhydride is added slowly to 19 ml offormic acid at ambient temperature. After one hour of stirring, asolution of 6.0 g of4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)aniline in 28 ml of formicacid is added dropwise. The mixture is stirred at ambient temperaturefor 2 h and then concentrated under vacuum and taken up with water. Theaqueous phase is neutralized with a saturated sodium bicarbonatesolution and extracted three times with 100 ml of dichloromethane. Theorganic phases are dried over magnesium sulfate, filtered andconcentrated under vacuum. The crude product is triturated with ethylether and the solid is filtered off, so as to obtain 5.0 g ofN-[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]formamide.

Example 9.2:N-[5-Methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]formamide

A mixture of 0.53 g of5-methyl-4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)aniline in 5.7 mlof formic acid is refluxed for 20 h. The mixture is cooled, diluted withwater and neutralized with a saturated sodium hydrogen carbonatesolution. The aqueous phase is extracted with ethyl acetate. The organicphase is dried over magnesium sulfate and concentrated under vacuum. Thecrude product is purified on 50 g of silica, elution being carried outwith methanol in dichloromethane (97/3 and 1% NH₄OH), so as to obtain0.56 g ofN-[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]formamide.

The compounds (IIIb) obtained according to Example 9 are described inTable 3.

TABLE 3 Compounds IIIb Name MS Method MH⁺ Tr IIIb-1N-{2-Methoxy-4-[1-(propan-2-yl)piperidin- D 277 0.834-yl]phenyl}formamide IIIb-2 N-[2-Methoxy-5-methyl-4-(1- A 263 0.28methylpiperidin-4-yl)phenyl]formamide IIIb-3N-[4-(1-Methylpiperidin-4-yl)-2-(propan-2- A 277 0.37yloxy)phenyl]formamide IIIb-4 2-Methylpropan-2-yl 4-[4-(formylamino)- A363 1.08 3-(propan-2-yloxy)phenyl]piperidine-1- carboxylate IIIb-5N-{2-(Propan-2-yloxy)-4-[1-(propan-2- A 305 0.44yl)piperidin-4-yl]phenyl}formamide IIIb-6N-[4-(1-Cyclopropylpiperidin-4-yl)-2- A 303 0.55(propan-2-yloxy)phenyl]formamide IIIb-7N-[5-Methyl-4-(1-methylpiperidin-4-yl)-2- A 291 0.39(propan-2-yloxy)phenyl]formamide IIIb-8N-[4-(5-Methoxy-1-methyl-1,2,3,6- A 305 0.40tetrahydropyridin-4-yl)-2-(propan-2- yloxy)phenyl]formamide IIIb-9N-[2-(Propan-2-yloxy)-4-(2,2,6,6- A 319 0.52 tetramethylpiperidin-4-yl)phenyl]formamide IIIb-10 N-[4-(1,2,2,6,6-Pentamethylpiperidin-4- A333 0.48 yl)-2-(propan-2-yloxy)phenyl]formamide IIIb-112-Methylpropan-2-yl 4-[4-(formylamino)- C 391 6.283-(propan-2-yloxy)phenyl]-2,6- dimethylpiperidine-1-carboxylate IIIb-122-Methylpropan-2-yl 2-ethyl-4-[4- C 391 6.26 (formylamino)-3-(propan-2-yloxy)phenyl]piperidine-1-carboxylate IIIb-13N-[4-(2-Ethyl-1-methylpiperidin-4-yl)-2- A 305 0.55(propan-2-yloxy)phenyl]formamide IIIb-14(cis)-4-[4-(Formylamino)-3-(propan-2- A 321 0.33 and 0.36yloxy)phenyl]-1-methylpiperidin-3-yl formate IIIb-15 2-Methylpropan-2-yl4-[4-(formylamino)- A 405 1.19 3-(propan-2-yloxy)phenyl]-2-(propan-2-yl)piperidine-1-carboxylate IIIb-16 2-{4-[4-(Formylamino)-3-(propan-2- A335 0.39 yloxy)phenyl]piperidin-1-yl}ethyl formate IIIb-17N-[5-Fluoro-4-(1-methylpiperidin-4-yl)-2- A 295 0.41(propan-2-yloxy)phenyl]formamide IIIb-18 N-[2-Methoxy-5-methyl-4-(1- A263 0.31 methylpiperidin-3-yl)phenyl]formamide IIIb-19N-[4-(1-Ethylpiperidin-3-yl)-2-(propan-2- A 291 0.41yloxy)phenyl]formamide IIIb-20 N-[4-(Octahydroindolizin-8-yl)-2-(propan-A 303 0.41 2-yloxy)phenyl]formamide IIIb-21N-{2-Methoxy-4-[4-(pyrrolidin-1- E 304 0.83yl)piperidin-1-yl]phenyl}formamide IIIb-22N-{2-Methyl-4-[4-(pyrrolidin-1-yl)piperidin- E 288 0.781-yl]phenyl}formamide IIIb-23 N-{2-Methoxy-4-[4-(propan-2-yl)piperazin-1-yl]phenyl}formamide IIIb-24N-[2-Methoxy-4-(4-methylpiperazin-1- A 250 0.20 yl)phenyl]formamideIIIb-25 N-[4-(4-Methylpiperazin-1-yl)-2-(propan- A 278 0.322-yloxy)phenyl]formamide IIIb-26N-[5-Methyl-4-(4-methylpiperazin-1-yl)-2- A 292 0.39(propan-2-yloxy)phenyl]formamide IIIb-27N-[4-(3,5-Dimethylpiperazin-1-yl)-2- A 292 0.39(propan-2-yloxy)phenyl]formamide IIIb-28 N-[2-(Propan-2-yloxy)-4-(3,4,5-A 306 0.38 trimethylpiperazin-1-yl)phenyl]formamide IIIb-29N-[4-(5,6-Dihydroimidazo[1,2-a]pyrazin- A 301 0.557(8H)-yl)-2-(propan-2- yloxy)phenyl]formamide IIIb-30N-{4-[3-(2-Hydroxyethyl)-4- D 322 0.93methylpiperazin-1-yl]-2-(propan-2- yloxy)phenyl}formamide IIIb-31N-{4-[3-(2-Methoxyethyl)-4- D 336 2.22methylpiperazin-1-yl]-2-(propan-2- yloxy)phenyl}formamide IIIb-32N-[4-(4-Methyl-1,4-diazepan-1-yl)-2- B 292 0.46(propan-2-yloxy)phenyl]formamide IIIb-33 N-{4-[(1S,4S)-5-Methyl-2,5- B290 0.43 diazabicyclo[2.2.1]hept-2-yl]-2-(propan-2-yloxy)phenyl}formamide IIIb-34N-{4-[3-(Dimethylamino)pyrrolidin-1-yl]-2- A 292 0.37(propan-2-yloxy)phenyl}formamide IIIb-35N-{4-[3-(Dimethylamino)pyrrolidin-1-yl]-5- D 306 2.58methyl-2-(propan-2- yloxy)phenyl}formamide IIIb-36N-{4-[3-(Diethylamino)pyrrolidin-1-yl]-2- D 320 2.26(propan-2-yloxy)phenyl}formamide IIIb-37N-[4-(1H-Imidazol-1-yl)-2-(propan-2- D 246 1.12 yloxy)phenyl]formamideIIIb-38 N-[4-(2-Methyl-1H-imidazol-1-yl)-2- A 260 0.36(propan-2-yloxy)phenyl]formamide IIIb-39N-[5-Methyl-4-(2-methyl-1H-imidazol-1- D 274 1.28yl)-2-(propan-2-yloxy)phenyl]formamide IIIb-40N-[4-(4-Methyl-1H-imidazol-1-yl)-2- D 260 1.61(propan-2-yloxy)phenyl]formamide IIIb-41N-[4-(2,4-Dimethyl-1H-imidazol-1-yl)-2- D 274 1.79(propan-2-yloxy)phenyl]formamide IIIb-42N-[2-(Propan-2-yloxy)-4-(1H-1,2,4-triazol- A 247 0.561-yl)phenyl]formamide IIIb-43 N-[4-{Methyl[2-(pyrrolidin-1- B 306 0.51yl)ethyl]amino}-2-(propan-2- yloxy)phenyl]formamide IIIb-44N-{4-[(8aR)-Hexahydropyrrolo[1,2- A 304 0.39a]pyrazin-2(1H)-yl]-2-(propan-2- yloxy)phenyl}formamide IIIb-45N-[4-(1-Formyl-1,7-diazaspiro[4.4]non-7- A 332 1.36yl)-2-(propan-2-yloxy)phenyl]formamide IIIb-46N-[4-(1-Ethyl-1,7-diazaspiro[4.4]non-7- B 332 0.55yl)-2-(propan-2-yloxy)phenyl]formamide IIIb-47N-[4-{(3R)-3-[Methyl(oxetan-3- B 348 0.52yl)amino]piperidin-1-yl}-2-(propan-2- yloxy)phenyl]formamide IIIb-48N-[4-(3-Methoxypyridin-4-yl)-2-(propan-2- A 287 0.47yloxy)phenyl]formamide IIIb-49 N-[4-(1-Methyl-1H-pyrazol-4-yl)-2- A 2600.66 (propan-2-yloxy)phenyl]formamide IIIb-50N-[4-(1-Methyl-1H-pyrazol-3-yl)-2- A 260 0.70(propan-2-yloxy)phenyl]formamide IIIb-51 N-[4-Methoxy-2-(propan-2- D 2100.38 yloxy)phenyl]formamide IIIb-52N-(1-Methyl-2-oxo-2,3,4,5-tetrahydro-1H- D 219 2.631-benzazepin-8-yl)formamide IIIb-53N-(1-Methyl-2-oxo-2,3,4,5-tetrahydro-1H- A 219 0.601-benzazepin-7-yl)formamide IIIb-54N-[6-(4-Methylpiperazin-1-yl)-4-(propan- D 279 0.322-yloxy)pyridin-3-yl]formamide IIIb-55N-[6-(1-Methylpiperidin-4-yl)-4-(propan-2- A 278 0.14yloxy)pyridin-3-yl]formamide IIIb-56N-[6-(4-Methylpiperazin-1-yl)-2-(propan- D 279 0.982-yloxy)pyridin-3-yl]formamide IIIb-57N-[6-(1-Methylpiperidin-4-yl)-2-(propan-2- D 278 1.93yloxy)pyridin-3-yl]formamide IIIb-58 2-Methylpropan-2-yl4-[5-(formylamino)- A 337 0.82 1-(propan-2-yl)-1H-pyrazol-3-yl]piperidine-1-carboxylate IIIb-59 2-Methylpropan-2-yl3-[5-(formylamino)- D 337 3.76 1-(propan-2-yl)-1H-pyrazol-3-yl]piperidine-1-carboxylate IIIb-60N-(1-Phenyl-1H-pyrazol-5-yl)formamide A 188 0.39 IIIb-61N-(3-Cyclopropyl-1-phenyl-1H-pyrazol-5- D 228 3.20 yl)formamide IIIb-62N-[1-(Propan-2-yl)-3-(pyridin-3-yl)-1H- A 231 0.29pyrazol-5-yl]formamide IIIb-63 N-[3-Cyclopropyl-1-(propan-2-yl)-1H- A194 0.49 pyrazol-5-yl]formamide IIIb-64N-[3-Methyl-1-(propan-2-yl)-1H-pyrazol- A 168 0.33 5-yl]formamideIIIb-65 N-[1-Methyl-2-oxo-6-(propan-2-yloxy)- A 277 0.812,3,4,5-tetrahydro-1H-1-benzazepin-7- yl]formamide IIIb-66N-{4-[(4-Methylpiperazin-1-yl)methyl]-2- A 292 0.47(propan-2-yloxy)phenyl}formamide IIIb-67N-[4-(3,5-Dimethyl-1H-1,2,4-triazol-1-yl)- A 275 0.782-(propan-2-yloxy)phenyl]formamide IIIb-68N-[5-(4-Methylpiperazin-1-yl)-2-(propan- B 278 0.552-yloxy)phenyl]formamide IIIb-69 N-[4-(Formylamino)-3-(propan-2- B 3070.82 yloxy)phenyl]-N-(tetrahydro-2H-pyran-4- yl)formamide IIIb-701-[4-(Formylamino)-3-(propan-2- A 321 0.87 yloxy)phenyl]piperidin-4-ylacetate IIIb-71 N-[4-(1-Methylpyrrolidin-3-yl)-2-(propan- D 263 0.882-yloxy)phenyl]formamide IIIb-72 N-[1-(Propan-2-yl)-3-(tetrahydro-2H- A238 0.66 pyran-4-yl)-1H-pyrazol-5-yl]formamide IIIb-73N-[4-(Formylamino)-3-(propan-2- A 320 0.52yloxy)phenyl]-N-(1-methylpiperidin-4- yl)formamide IIIb-742-Methylpropan-2-yl 4-[1-cyclobutyl-5- B 349 1.26(formylamino)-1H-pyrazol-3-yl]piperidine- 1-carboxylate IIIb-75N-[3-(4-Methylpiperazin-1-yl)-2-(propan- B 278 0.552-yloxy)phenyl]formamide IIIb-76 N-(5-Methyl-2,3,4,5-tetrahydro-1,5- D207 1.49 benzoxazepin-7-yl)formamide IIIb-77N-[4-(4-Ethylpiperazin-1-yl)-2-(propan-2- A 292 0.65yloxy)phenyl]formamide IIIb-78 N-[1-Methyl-2-oxo-8-(propan-2-yloxy)- D277 3.16 2,3,4,5-tetrahydro-1H-1-benzazepin-7- yl]formamide IIIb-79N-[4-Chloro-2-(propan-2- A 214 1.19 yloxy)phenyl]formamide IIIb-80N-[4-(1-Methyl-1,7-diazaspiro[4.4]non-7- A 318 0.69yl)-2-(propan-2-yloxy)phenyl]formamide

V—Preparation of the Compounds of Formula (I) Example 10:7-(2-Methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)-phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide(I-16)

A mixture of 527 mg ofN-[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]formamide and 953mg of1-[N-(2-methylpropan-2-yl)-P,P-di(pyrrolidin-1-yl)phosphorimidoyl]-pyrrolidine(BTPP) in 10 ml of anhydrous DMF is stirred at ambient temperature for30 min, and then a solution of 577 mg of methyl7-(2-methoxyphenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylatein 15 ml of anhydrous DMF is slowly added. The mixture is stirred atambient temperature for 48 h, and then diluted with ethyl acetate andwashed three times with water. The organic phase is dried over magnesiumsulfate, filtered and concentrated under vacuum. The crude product ispurified on 80 g of silica, elution being carried out with 5-10% ofmethanol in dichloromethane, so as to obtain 615 mg of methyl7-(2-methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxylatein the form of a yellow solid.

The crude product is diluted with 600 ml of 7N ammoniacal methanol andthe solution is stirred at ambient temperature for 48 h, and thenconcentrated under vacuum. The residue is solubilized with 100 ml of hotethyl acetate and the solution is left to cool in order to obtain asuspension. The suspension is cooled in an ice bath and filtered. Thesolid is washed with ethyl ether and dried under vacuum, so as to obtain477 mg of7-(2-methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamidein the form of a yellow solid.

Example 11:2-{[4-(1-Methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-6-carboxamide(I-76)

123 mg of N,N-diisopropylethylamine, 181 mg of HATU and 14 mg ofammonium chloride are added to a solution of 117 mg of2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-6-carboxylicacid in 6 ml of dimethylformamide. The reaction medium is stirred for 16hours at ambient temperature and then concentrated to dryness underreduced pressure. Purification is carried out by flash chromatography onalumina, elution being carried out with a mixture of dichloromethane andmethanol (+10% NH₄OH) (95/5). The product resulting from the columnpurification is taken up in methanol and is purified by preparative thinlayer chromatography (eluent: dichloromethane/methanol (+10% NH₄OH)(95/5)), so as to give 23 mg of2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-6-carboxamidein the form of a yellow solid.

Example 12:7-(4-Fluorophenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide(I-12)

27 mg of sodium hydride (at 60%) are added to a solution of 126 mg ofN-[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]formamide in 2 mlof dimethylformamide. The suspension is stirred at ambient temperaturefor 30 min, and is then diluted with 1 ml of dimethylformamide, and asolution of 80 mg of7-(4-fluorophenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxamidein 2 ml of dimethylformamide is added. The mixture is stirred at ambienttemperature for 30 min, and then diluted with 50 ml of methanol. Themixture is stirred at ambient temperature for 1 h, and then concentratedunder vacuum. The residue is purified on 40 g of silica, elution beingcarried out with 0-20% of methanol in dichloromethane, and then by highperformance liquid chromatography (Macherey-Nagel 250×40 mm reversephase C18 Nucleodur 10μ column. Eluent: MeCN containing 0.07% TFA andH₂O containing 0.07% TFA. 10% MeCN hold: 3 min, gradient up to 95% MeCNin 37 min and then 95% MeCN hold of 8 min. Flow rate: 70 ml/min). Thefractions containing the expected material are loaded on to a 2 g VarianBond Elut SCX cartraige (preconditioned with MeOH). Washing thecartridge four times with methanol, followed by elution of the expectedmaterial with 2N ammonia in methanol gives, after drying, 10 mg of7-(4-fluorophenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide.

The compounds (I′) obtained according to Examples 10 to 12 are describedin Table 4.

TABLE 4 MS Compound Compound Compound conditions/ I′ II IIIb Name NMRMH+/Tr I-1 II-1 IIIb-21 2-({2-Methoxy-4-[4- 1.85 to 2.25 (m, 8 H); 2.88(m, 1 H); E (pyrrolidin-1-yl)piperidin- 3.10 (m, 2 H); 3.23 to 3.858(partially 529 1-yl]phenyl}amino)-7- masked m, 6 H); 3.87 (s, 3 H); 6.55to 0.78 phenylthieno[3,2- 7.00 (broad m, 2 H); 7.48 (t, J = 7.7 Hz,d]pyrimidine-6- 1 H); 7.53 (t, J = 7.7 Hz, 2 H); carboxamide 7.58 (broads, 1 H); 7.68 (d, J = 7.7 Hz, 2 H); 7.87 (broad s, 1 H); 8.02 (broad m,1 H); 8.11 (broad s, 1 H); 9.21 (s, 1 H); 10.48 (broad m, 1 H) I-2 II-1IIIb-22 2-({2-Methyl-4-[4- 1.82 to 2.27 (m, 8 H); 2.20 (s, 3 H); E(pyrrolidin-1-yl)piperidin- 2.85 (m, 1 H); 3.10 (m, 2 H); 3.25 to 5131-yl]phenyl}amino)-7- 3.85 (partially masked m, 6 H); 6.80 to 0.70phenylthieno[3,2- 7.10 (broad m, 2 H); 7.38 to 7.55 (m, 5 H);d]pyrimidine-6- 7.60 (d, J = 7.7 Hz, 2 H); 7.84 (m, 1 H); carboxamide8.70 (s, 1 H); 9.16 (s, 1 H); 10.68 (broad m, 1 H) I-3 II-3 IIIb-217-(3-Chlorophenyl)-2-({2- 1.78 to 2.30 (m, 8 H); 2.93 to 3.85 (m, 9 Emethoxy-4-[4-(pyrrolidin- H); 3.81 (s, 3 H); 6.70 to 7.20 (broad m, 5631-yl)piperidin-1- 2 H); 7.45 (m, 3 H); 7.70 (s, 1 H); 1.03yl]phenyl}amino)thieno[3, 7.79 (s, 1 H); 7.83 (s, 1 H); 8.09 (m, 1 H);2-d]pyrimidine-6- 8.20 (s, 1 H); 9.19 (s, 1 H); 11.08 (broad carboxamidem, 1 H) I-4 II-4 IIIb-21 7-(4-Chlorophenyl)-2-({2- 1.80 to 2.23 (m, 8H); 2.65 to E methoxy-4-[4-(pyrrolidin- 3.90 (partially masked m, 9 H);3.82 (s, 3 H); 563 1-yl)piperidin-1- 6.45 to 6.90 (broad m, 2 H); 7.58(d, J = 8.8 Hz, 1.05 yl]phenyl}amino)thieno[3, 2 H); 7.67 (d, J = 8.8Hz, 2 H); 2-d]pyrimidine-6- 7.77 (s, 1 H); 7.87 (m, 2 H); 8.12 (s, 1carboxamide H); 9.19 (s, 1 H); 11.70 (broad m, 1 H) I-5 II-27 IIIb-212-({2-Methoxy-4-[4- 1.83 to 2.40 (m, 8 H); 3.00 to 3.92 (m, 9 E(pyrrolidin-1-yl)piperidin- H); 3.85 (s, 3 H); 6.70 to 7.22 (broad m,535 1-yl]phenyl}amino)-7- 2 H); 7.52 (d, J = 4.0 Hz, 1 H); 7.69 (m, 0.68(thiophen-3-yl)thieno[3,2- 1 H); 7.82 (s, 1 H); 7.98 (s, 1 H);d]pyrimidine-6- 8.07 (m, 1 H); 8.10 (broad m, 1 H); 8.30 (s, 1carboxamide H); 9.21 (s, 1 H); 11.09 (broad m, 1 H) I-6 II-28 IIIb-212-({2-Methoxy-4-[4- 1.88 to 2.34 (m, 8 H); 3.00 to 3.94 (m, 9 E(pyrrolidin-1-yl)piperidin- H); 3.89 (s, 3 H); 6.78 to 7.22 (broad m,535 1-yl]phenyl}amino)-7- 2 H); 7.20 (m, 1 H); 7.63 (m, 1 H); 0.69(thiophen-2-yl)thieno[3,2- 7.72 (m, 1 H); 8.02 (s, 1 H); 8.10 (s, 1 H);d]pyrimidine-6- 8.22 (broad m, 1 H); 8.31 (s, 1 H); carboxamide 9.21 (s,1 H); 11.94 (broad m, 1 H) I-7 II-1 IIIb-23 2-({2-Methoxy-4-[4- 1.31 (d,J = 6.0 Hz, 6 H); 3.15 (m, 4 H); E (propan-2-yl)piperazin-1- 3.50 (m, 3H); 3.80 (m, 2 H); 3.84 (s, 3 503 yl]phenyl}amino)-7- H); 6.48 (broad d,J = 8.5 Hz, 1 H); 0.81 phenylthieno[3,2- 6.70 (broad s, 1 H); 7.46 (t, J= 7.6 Hz, 1 H); d]pyrimidine-6- 7.51 (t, J = 7.6 Hz, 2 H); 7.58 (broads, carboxamide 1 H); 7.66 (d, J = 7.6 Hz, 2 H); 7.85 (broad s, 1 H);7.98 (d, J = 8.5 Hz, 1 H); 8.10 (broad s, 1 H); 9.20 (s, 1 H); 10.55(broad m, 1 H) I-8 II-1 IIIb-1 2-({2-Methoxy-4-[1- 1.00 (d, J = 6.4 Hz,6 H); 1.55 to 1.69 (m, A (propan-2-yl)piperidin-4- 2 H); 1.69 to 1.78(m, 2 H); 2.13 to 502 yl]phenyl}amino)-7- 2.25 (m, 2 H); 2.35 to 2.47(m, 1 H); 0.65 phenylthieno[3,2- 2.70 (quin, J = 6.6 Hz, 1 H); 2.82 to2.94 (m, 2 d]pyrimidine-6- H); 3.85 (s, 3 H); 6.71 (dd, J = 1.5 andcarboxamide 8.3 Hz, 1 H); 6.89 (d, J = 1.5 Hz, 1 H); 7.40 to 7.59 (m, 4H); 7.65 (d, J = 6.8 Hz, 2 H); 7.84 (broad s, 1 H); 8.05 (s, 1 H); 8.12(d, J = 8.3 Hz, 1 H); 9.23 (s, 1 H) I-9 II-5 IIIb-257-(2-Methoxyphenyl)-2- 1.26 (d, J = 6.1 Hz, 6 H); 2.23 (s, 3 H); A{[4-(4-methylpiperazin-1- 2.42 to 2.48 (m, 4 H); 3.01 to 3.10 (m, 4 533yl)-2-(propan-2- H); 3.70 (s, 3 H); 4.65 (quin, J = 6.1 Hz, 1 0.65yloxy)phenyl]amino}thieno[3, H); 6.30 (dd, J = 2.4 and 8.8 Hz, 1 H);2-d]pyrimidine-6- 6.61 (d, J = 2.4 Hz, 1 H); 6.82 to 6.93 (m,carboxamide 1 H); 7.12 (t, J = 7.2 Hz, 1 H); 7.18 (d, J = 8.1 Hz, 1 H);7.42 to 7.53 (m, 2 H); 7.71 (broad s, 1 H); 7.77 (s, 1 H); 7.97 (d, J =9.0 Hz, 1 H); 9.16 (s, 1 H) I-10 II-12 IIIb-25 7-(4-Fluoro-3- 1.25 (d, J= 6.1 Hz, 6 H); 2.23 (s, 3 H); A methoxyphenyl)-2-{[4-(4- 2.44 to 2.48(m, 4 H); 3.02 to 3.12 (m, 4 551 methylpiperazin-1-yl)-2- H); 3.82 (s, 3H); 4.65 (quin, J = 5.9 Hz, 1 0.67 (propan-2- H); 6.37 (dd, J = 2.3 and8.9 Hz, 1 H); yloxy)phenyl]amino}thieno[3, 6.64 (d, J = 2.2 Hz, 1 H);7.17 (ddd, 2-d]pyrimidine-6- J = 2.0 and 4.3 and 8.4 Hz, 1 H);carboxamide 7.35 (dd, J = 8.3 and 11.5 Hz, 1 H); 7.46 (dd, J = 2.0 and8.6 Hz, 1 H); 7.59 (broad s, 1 H); 7.86 (broad s, 1 H); 7.91 (s, 1 H);8.01 (d, J = 8.1 Hz, 1 H); 9.19 (s, 1 H) I-11 II-7 IIIb-257-(4-Methoxyphenyl)-2- 1.27 (d, J = 5.9 Hz, 6 H); 2.24 (s, 3 H); A{[4-(4-methylpiperazin-1- 2.44 to 2.48 (m, 4 H); 3.06 to 3.12 (m, 4 533yl)-2-(propan-2- H); 3.84 (s, 3 H); 4.66 (spt, J = 6.1 Hz, 1 0.67yloxy)phenyl]amino}thieno[3, H); 6.43 (dd, J = 2.4 and 8.8 Hz, 1 H);2-d]pyrimidine-6- 6.64 (d, J = 2.2 Hz, 1 H); 7.09 (d, J = 8.6 Hz,carboxamide 2 H); 7.46 (broad s, 1 H); 7.60 (d, J = 8.6 Hz, 2 H); 7.81(broad s, 1 H); 7.84 (s, 1 H); 8.06 (d, J = 8.8 Hz, 1 H); 9.16 (s, 1 H)I-12 II-17 IIIb-25 7-(4-Fluorophenyl)-2-{[4- 1.27 (d, J = 5.9 Hz, 6 H);2.23 (s, 3 H); A (4-methylpiperazin-1-yl)- 2.43 to 2.48 (m, 4 H); 3.05to 3.12 (m, 4 521 2-(propan-2- H); 4.66 (spt, J = 6.1 Hz, 1 H); 6.44(dd, 0.67 yloxy)phenyl]amino}thieno[3, J = 2.4 and 8.8 Hz, 1 H); 6.64(d, J = 2.4 Hz, 2-d]pyrimidine-6- 1 H); 7.32 to 7.40 (m, 2 H); 7.62 tocarboxamide 7.73 (m, 3 H); 7.83 (broad s, 1 H); 7.87 (s, 1 H); 8.01 (d,J = 8.8 Hz, 1 H); 9.19 (s, 1 H) I-13 II-1 IIIb-22-{[2-Methoxy-5-methyl-4- 1.49 to 1.80 (m, 4 H); 1.89 to 2.05 (m, 2 A(1-methylpiperidin-4- H); 2.13 (s, 3 H); 2.20 (s, 3 H); 2.53 to 488yl)phenyl]amino}-7- 2.64 (m, 1 H); 2.87 (d, J = 11.2 Hz, 2 H); 0.62phenylthieno[3,2- 3.83 (s, 3 H); 6.82 (s, 1 H); 7.38 to d]pyrimidine-6-7.57 (m, 4 H); 7.59 to 7.70 (m, J = 6.8 Hz, 2 carboxamide H); 7.85(broad s, 1 H); 8.00 (d, J = 9.3 Hz, 2 H); 9.23 (s, 1 H) I-14 II-10IIIb-24 7-(4-Fluoro-2- 2.23 (s, 3 H); 2.42 to 2.49 (m, 4 H); 3.04 Amethoxyphenyl)-2-{[2- to 3.14 (m, 4 H); 3.70 (s, 3 H); 3.80 (s, 3 523methoxy-4-(4- H); 6.37 (dd, J = 2.4 and 9.0 Hz, 1 H); 0.57methylpiperazin-1- 6.61 (d, J = 2.4 Hz, 1 H); 6.94 (td, J = 2.4yl)phenyl]amino}thieno[3, and 8.4 Hz, 1 H); 7.01 to 7.16 (m, 2 H);2-d]pyrimidine-6- 7.46 (dd, J = 7.1 and 8.6 Hz, 1 H); carboxamide 7.72(broad s, 1 H); 7.80 (d, J = 8.6 Hz, 1 H); 7.96 (s, 1 H); 9.14 (s, 1 H)I-15 II-6 IIIb-24 2-{[2-Methoxy-4-(4- 2.23 (s, 3 H); 2.45 to 2.49 (m, 4H); 3.08 A methylpiperazin-1- to 3.13 (m, 4 H); 3.79 (s, 3 H); 3.81 (s,3 505 yl)phenyl]amino}-7-(3- H); 6.37 (dd, J = 2.3 and 8.7 Hz, 1 H);0.58 methoxyphenyl)thieno[3,2- 6.63 (d, J = 2.4 Hz, 1 H); 7.02 (dd, J =2.2 d]pyrimidine-6- and 8.1 Hz, 1 H); 7.18 (d, J = 7.8 Hz, 1 carboxamideH); 7.24 (s, 1 H); 7.41 (t, J = 7.8 Hz, 1 H); 7.59 (broad s, 1 H); 7.83to 7.94 (m, 2 H); 8.04 (s, 1 H); 9.17 (s, 1 H) I-16 II-5 IIIb-37-(2-Methoxyphenyl)-2- 1.29 (d, J = 6.1 Hz, 6 H); 1.56 to 1.74 (m, A{[4-(1-methylpiperidin-4- 4 H); 1.88 to 1.98 (m, 2 H); 2.19 (s, 3 532yl)-2-(propan-2- H); 2.30 to 2.43 (m, 1 H); 2.80 to 0.69yloxy)phenyl]amino}thieno[3, 2.90 (m, 2 H); 3.70 (s, 3 H); 4.67 (spt, J= 6.0 Hz, 2-d]pyrimidine-6- 1H); 6.60 (d, J = 8.3 Hz, 1 H); carboxamide6.87 (d, J = 1.2 Hz, 1 H); 6.90 (broad s, 1 H); 7.13 (t, J = 7.3 Hz, 1H); 7.20 (d, J = 8.1 Hz, 1 H); 7.36 to 7.58 (m, 2 H); 7.73 (broad s, 1H); 7.86 (s, 1 H); 8.13 (d, J = 8.3 Hz, 1 H); 9.21 (s, 1 H) I-17 II-1IIIb-7 2-{[5-Methyl-4-(1- 1.29 (d, J = 5.9 Hz, 6 H); 1.53 to 1.75 (m, Amethylpiperidin-4-yl)-2- 4 H); 1.96 (td, J = 2.9 and 11.1 Hz, 2 H); 516(propan-2- 2.12 (s, 3 H); 2.19 (s, 3 H); 2.53 to 0.67yloxy)phenyl]amino}-7- 2.60 (m, 1 H); 2.82 to 2.91 (m, 2 H);phenylthieno[3,2- 4.63 (quin, J = 6.1 Hz, 1 H); 6.82 (s, 1 H); 7.38d]pyrimidine-6- to 7.58 (m, 4 H); 7.67 (d, J = 7.3 Hz, 2 carboxamide H);7.80 to 7.95 (m, 2 H); 8.12 (s, 1 H); 9.25 (s, 1 H) I-18 II-1 IIIb-182-{[2-Methoxy-5-methyl-4- 1.35 to 1.48 (m, 1 H); 1.54 to 1.74 (m, 3 A(1-methylpiperidin-3- H); 1.90 (t, J = 11.0 Hz, 2 H); 2.14 (s, 3 488yl)phenyl]amino}-7- H); 2.18 (s, 3 H); 2.64 to 2.92 (m, 3 H); 0.64phenylthieno[3,2- 3.83 (s, 3 H); 6.83 (s, 1 H); 7.42 to d]pyrimidine-6-7.56 (m, 4 H); 7.65 (d, J = 7.8 Hz, 2 H); carboxamide 7.87 (broad s, 1H); 8.00 (s, 1 H); 8.03 (s, 1 H); 9.24 (s, 1 H) I-19 II-29 IIIb-32-{[4-(1-Methylpiperidin-4- 1.28 (d, J = 5.9 Hz, 6 H); 1.57 to 1.76 (m,A yl)-2-(propan-2- 4 H); 1.86 to 2.00 (m, 2 H); 2.19 (s, 3 506yloxy)phenyl]amino}-7-(1- H); 2.35 to 2.45 (m, 1 H); 2.80 to 0.61methyl-1H-pyrazol-5- 2.90 (m, 2 H); 3.69 (s, 3 H); 4.66 (quin, J = 6.1Hz, yl)thieno[3,2-d]pyrimidine- 1 H); 6.47 (d, J = 2.0 Hz, 1 H);6-carboxamide 6.67 (dd, J = 1.7 and 8.3 Hz, 1 H); 6.89 (d, J = 1.5 Hz, 1H); 7.44 (broad s, 1 H); 7.58 (d, J = 2.0 Hz, 1 H); 7.93 (broad s, 1 H);8.00 (d, J = 8.3 Hz, 1 H); 8.05 (s, 1 H); 9.26 (s, 1 H) I-20 II-15IIIb-3 7-(2-Ethoxyphenyl)-2-{[4- 1.13 (t, J = 7.0 Hz, 3 H); 1.29 (d, J =6.1 Hz, A (1-methylpiperidin-4-yl)-2- 6 H); 1.56 to 1.74 (m, 4 H); 1.88to 546 (propan-2- 1.98 (m, 2 H); 2.19 (s, 3 H); 2.29 to 0.72yloxy)phenyl]amino}thieno[3, 2.43 (m, 1 H); 2.80 to 2.88 (m, 2 H); 4.00(q, 2-d]pyrimidine-6- J = 7.1 Hz, 2 H); 4.67 (quin, J = 6.1 Hz, 1carboxamide H); 6.60 (dd, J = 1.5 and 8.3 Hz, 1 H); 6.87 (d, J = 1.5 Hz,1 H); 6.91 (broad s, 1 H); 7.06 to 7.21 (m, 2 H); 7.40 to 7.52 (m, 2 H);7.73 (broad s, 1 H); 7.86 (s, 1 H); 8.15 (d, J = 8.3 Hz, 1 H); 9.21 (s,1 H) I-21 II-6 IIIb-3 7-(3-Methoxyphenyl)-2- 1.30 (d, J = 5.9 Hz, 6 H);1.55 to 1.82 (m, A {[4-(1-methylpiperidin-4- 4 H); 1.93 to 2.08 (m, 2H); 2.22 (broad 532 yl)-2-(propan-2- s, 3 H); 2.35 to 2.47 (m, 1 H);2.81 to 0.70 yloxy)phenyl]amino}thieno[3, 2.98 (m, 2 H); 3.81 (s, 3 H);4.68 (quin, 2-d]pyrimidine-6- J = 5.4 Hz, 1 H); 6.66 (d, J = 8.1 Hz, 1H); carboxamide 6.90 (s, 1 H); 7.06 (dd, J = 2.0 and 8.3 Hz, 1 H); 7.21(d, J = 7.8 Hz, 1 H); 7.28 (d, J = 1.7 Hz, 1 H); 7.44 (t, J = 7.8 Hz, 1H); 7.56 (broad s, 1 H); 7.87 (broad s, 1 H); 7.95 (s, 1 H); 8.27 (d, J= 8.3 Hz, 1 H); 9.24 (s, 1 H) I-22 II-50 IIIb-7 2-{[5-Methyl-4-(1- 1.30(d, J = 5.9 Hz, 6 H); 1.55 to 1.82 (m, B methylpiperidin-4-yl)-2- 4 H);1.93 to 2.08 (m, 2 H); 2.22 (broad 517 (propan-2- s, 3 H); 2.35 to 2.47(m, 1 H); 2.81 to 0.78 yloxy)phenyl]amino}-7- 2.98 (m, 2 H); 3.81 (s, 3H); 4.68 (quin, (pyridin-2-yl)thieno[3,2- J = 5.4 Hz, 1 H); 6.66 (d, J =8.1 Hz, 1 H); d]pyrimidine-6- 6.90 (s, 1 H); 7.06 (dd, J = 2.0 and 8.3Hz, carboxamide 1 H); 7.21 (d, J = 7.8 Hz, 1 H); 7.28 (d, J = 1.7 Hz, 1H); 7.44 (t, J = 7.8 Hz, 1 H); 7.56 (broad s, 1 H); 7.87 (broad s, 1 H);7.95 (s, 1 H); 8.27 (d, J = 8.3 Hz, 1 H); 9.24 (s, 1 H) I-23 II-1IIIb-32 2-{[4-(4-Methyl-1,4- 1.25 (d, J = 6.1 Hz, 6 H); 1.89 (dq, J =5.7 A diazepan-1-yl)-2-(propan- and 5.9 Hz, 2 H); 2.27 (s, 3 H); 2.45(m, 517 2-yloxy)phenyl]amino}-7- 2 H); 2.62 (m, 2 H); 3.31 to 0.68phenylthieno[3,2- 3.51 (masked m, 4 H); 4.60 (qd, J = 5.9 andd]pyrimidine-6- 6.0 Hz, 1 H); 6.17 (dd, J = 2.4 and 9.3 Hz, carboxamide1 H); 6.34 (d, J = 2.7 Hz, 1 H); 7.43 (m, 1 H); 7.51 (m, 3 H); 7.66 (d,J = 6.8 Hz, 2 H); 7.76 to 7.89 (m, 3 H); 9.14 (s, 1 H) I-24 II-13 IIIb-37-(2-Fluoro-5- 1.29 (d, J = 5.9 Hz, 6 H); 1.65 (m, 4 H); Amethoxyphenyl)-2-{[4-(1- 1.95 (m, 2 H); 2.19 (s, 3 H); 2.37 (m, 1 550methylpiperidin-4-yl)-2- H); 2.85 (m, 2 H); 3.79 (s, 3 H); 0.70(propan-2- 4.67 (quin, J = 6.1 Hz, 1 H); 6.62 (dd, J = 2.0yloxy)phenyl]amino}thieno[3, and 8.3 Hz, 1 H); 6.89 (s, 1 H); 7.08 (dt,2-d]pyrimidine-6- J = 3.5 and 9.0 Hz, 1 H); 7.20 (dd, J = 3.2carboxamide and 5.9 Hz, 1 H); 7.27 (t, J = 9.3 Hz, 1 H); 7.56 (broad s,1 H); 7.77 (broad s, 1 H); 7.96 (s, 1 H); 8.19 (d, J = 8.3 Hz, 1 H);9.26 (s, 1 H) I-25 II-23 IIIb-3 7-(3-Cyanophenyl)-2-{[4- 1.30 (d, J =5.9 Hz, 6 H); 1.59 to 1.76 (m, A (1-methylpiperidin-4-yl)-2- 4 H); 1.95(td, J = 2.9 and 11.6 Hz, 2 H); 527 (propan-2- 2.19 (s, 3 H); 2.39 (m, 1H); 2.85 (d, 0.68 yloxy)phenyl]amino}thieno[3, J = 11.2 Hz, 2 H); 4.68(spt, J = 6.2 Hz, 1 2-d]pyrimidine-6- H); 6.81 (dd, J = 2.0 and 8.3 Hz,1 H); carboxamide 6.92 (d, J = 2.2 Hz, 1 H); 7.72 (t, J = 7.8 Hz, 1 H);7.91 (m, 4 H); 8.03 (s, 1 H); 8.17 (m, 2 H); 9.27 (s, 1 H) I-26 II-19IIIb-3 2-{[4-(1-Methylpiperidin-4- 1.28 (d, J = 5.9 Hz, 6 H); 1.59 to1.78 (m, A yl)-2-(propan-2- 4 H); 2.11 (m, 2 H); 2.28 (broad s, 3 H);586 yloxy)phenyl]amino}-7-[2- 2.42 (m, 1 H); 2.95 (m, 2 H); 4.66 (spt,0.76 (trifluoromethoxy)phenyl]thieno[3, J = 6.0 Hz, 1 H); 6.61 (dd, J =1.7 and 8.1 Hz, 2-d]pyrimidine-6- 1 H); 6.88 (d, J = 2.0 Hz, 1 H);carboxamide 7.46 (broad s, 1 H); 7.50 (dt, J = 1.6 and 8.1 Hz, 1 H);7.56 (td, J = 1.2 and 7.3 Hz, 1 H); 7.62 (td, J = 2.0 and 7.6 Hz, 1 H);7.69 (dd, J = 2.0 and 7.3 Hz, 1 H); 7.75 (broad s, 1 H); 7.93 (s, 1 H);8.07 (d, J = 8.3 Hz, 1 H); 9.26 (s, 1 H) I-27 II-1 IIIb-32-{[4-(1-Methylpiperidin-4- 1.30 (d, J = 6.1 Hz, 6 H); 1.57 to 1.75 (m,A yl)-2-(propan-2- 4 H); 1.94 (td, J = 2.4 and 11.4 Hz, 2 H); 502yloxy)phenyl]amino}-7- 2.19 (s, 3 H); 2.39 (m, 1 H); 2.86 (m, 2 0.69phenylthieno[3,2- H); 4.68 (spt, J = 6.1 Hz, 1 H); 6.68 (dd,d]pyrimidine-6- J = 1.6 and 8.4 Hz, 1 H); 6.90 (d, J = 2.0 Hz,carboxamide 1 H); 7.47 (t, J = 7.3 Hz, 1 H); 7.55 (m, 3 H); 7.67 (d, J =7.1 Hz, 2 H); 7.85 (broad s, 1 H); 7.94 (s, 1 H); 8.24 (d, J = 8.3 Hz, 1H); 9.24 (s, 1 H) I-28 II-1 IIIb-33 2-({4-[(1S,4S)-5-methyl- 1.25 (d, J= 5.9 Hz, 6 H); 1.74 to 1.98 (m, A 2,5- 2 H); 2.33 (broad s, 3 H); 2.61(broad s, 515 diazabicyclo[2.2.1]hept-2- 1 H); 2.82 (m, 1 H); 3.13 (m, 1H); 0.66 yl]-2-(propan-2- 3.32 (masked m, 1 H); 3.51 (broad s, 1 H);yloxy)phenyl}amino)-7- 4.30 (broad s, 1 H); 4.61 (m, 1 H);phenylthieno[3,2- 6.07 (d, J = 9.1 Hz, 1 H); 6.26 (broad s, 1 H);d]pyrimidine-6- 7.32 to 7.60 (m, 4 H); 7.66 (d, J = 7.4 Hz, carboxamide2 H); 7.76 to 7.97 (m, 3 H); 9.14 (s, 1 H) I-29 II-1 IIIb-34 2-({4-[3-1.26 (d, J = 5.9 Hz, 6 H); 1.79 (m, 1 H); A (Dimethylamino)pyrrolidin-2.12 (m, 1 H); 2.21 (s, 6 H); 2.79 (m, 1 517 1-yl]-2-(propan-2- H); 3.02(t, J = 8.4 Hz, 1 H); 0.68 yloxy)phenyl}amino)-7- 3.25 (masked m, 2 H);3.41 (m, 1 H); phenylthieno[3,2- 4.63 (m, 1 H); 6.03 (dd, J = 2.7 and8.8 Hz, 1 d]pyrimidine-6- H); 6.23 (d, J = 2.2 Hz, 1 H); 7.39 tocarboxamide 7.57 (m, 4 H); 7.66 (d, J = 7.1 Hz, 2 H); 7.79 (s, 1 H);7.81 (broad s, 1 H); 7.92 (d, J = 8.3 Hz, 1 H); 9.14 (s, 1 H) I-30 II-5IIIb-7 7-(2-Methoxyphenyl)-2- 1.28 (d, J = 5.9 Hz, 6 H); 1.54 to 1.71(m, A {[5-methyl-4-(1- 4 H); 1.95 (m, 2 H); 2.04 (s, 3 H); 546methylpiperidin-4-yl)-2- 2.19 (s, 3 H); 2.54 (masked m, 1 H); 2.85 (d,0.67 (propan-2- J = 11.0 Hz, 2 H); 3.69 (s, 3 H); 4.62 (m,yloxy)phenyl]amino}thieno[3, 1 H); 6.79 (s, 1 H); 6.82 (broad s, 1 H);2-d]pyrimidine-6- 7.13 (t, J = 7.3 Hz, 1 H); 7.20 (d, J = 8.1 Hz,carboxamide 1 H); 7.48 (m, 2 H); 7.74 (broad s, 1 H); 7.81 (s, 1 H);8.02 (s, 1 H); 9.21 (s, 1 H) I-31 II-1 IIIb-51 2-{[4-Methoxy-2-(propan-1.28 (d, J = 6.1 Hz, 6 H); 3.73 (s, 3 H); A 2-yloxy)phenyl]amino}-7-4.64 (spt, J = 6.0 Hz, 1 H); 6.40 (dd, 435 phenylthieno[3,2- J = 2.3 and8.9 Hz, 1 H); 6.63 (d, J = 2.2 Hz, 1.06 d]pyrimidine-6- 1 H); 7.46 (t, J= 7.1 Hz, 1 H); carboxamide 7.53 (m, 3 H); 7.66 (d, J = 7.3 Hz, 2 H);7.83 (broad s, 1 H); 7.90 (s, 1 H); 8.09 (d, J = 8.8 Hz, 1 H); 9.20 (s,1 H) I-32 II-25 IIIb-3 2-{[4-(1-Methylpiperidin-4- 1.29 (d, J = 5.9 Hz,6 H); 1.55 to 1.78 (m, A yl)-2-(propan-2- 4 H); 1.91 to 2.02 (m, 2 H);2.20 (s, 3 564 yloxy)phenyl]amino}-7-[3- H); 2.34 to 2.45 (m, 1 H); 2.79(s, 3 H); 0.62 (methylsulfinyl)phenyl]thieno[3, 2.82 to 2.93 (m, 2 H);4.68 (spt, J = 5.9 Hz, 2-d]pyrimidine-6- 1 H); 6.72 (dd, J = 1.5 and 8.3Hz, 1 carboxamide H); 6.89 (d, J = 1.2 Hz, 1 H); 7.67 to 7.81 (m, 4 H);7.88 (broad s, 1 H); 7.92 to 8.01 (m, 2 H); 8.16 (d, J = 8.3 Hz, 1 H);9.27 (s, 1 H) I-33 II-31 IIIb-3 7-(2-Methoxypyridin-3-yl)- 1.29 (d, J =6.1 Hz, 6 H); 1.53 to 1.77 (m, A 2-{[4-(1-methylpiperidin-4- 4 H); 1.91to 2.05 (m, 2 H); 2.21 (s, 3 533 yl)-2-(propan-2- H); 2.34 to 2.46 (m, 1H); 2.78 to 0.64 yloxy)phenyl]amino}thieno[3, 2.95 (m, 2 H); 3.80 (s, 3H); 4.67 (spt, J = 6.1 Hz, 2-d]pyrimidine-6- 1 H); 6.64 (d, J = 8.3 Hz,1 H); carboxamide 6.88 (s, 1 H); 7.18 (dd, J = 5.0 and 7.2 Hz, 1 H);7.47 (broad s, 1 H); 7.70 (broad s, 1 H); 7.86 to 7.95 (m, 2 H); 8.11(d, J = 8.1 Hz, 1 H); 8.28 (dd, J = 1.7 and 4.9 Hz, 1 H); 9.23 (s, 1 H)I-34 II-22 IIIb-3 7-(2-Cyanophenyl)-2-{[4- 1.31 (d, J = 6.1 Hz, 6 H);1.62 to 1.80 (m, A (1-methylpiperidin-4-yl)-2- 4 H); 2.03 (m, 2 H); 2.24(s, 3 H); 525 (propan-2- 2.44 (partially masked m, 1 H); 2.91 (m, 2 H);0.64 yloxy)phenyl]amino}thieno[3, 4.70 (m, 1 H); 6.81 (dd, J = 1.3 and8.6 Hz, 2-d]pyrimidine-6- 1 H); 6.95 (d, J = 1.3 Hz, 1 H); carboxamide7.64 (t, J = 7.8 Hz, 1 H); 7.78 (t, J = 7.8 Hz, 1 H); 7.88 (d, J = 7.8Hz, 1 H); 8.13 (s, 1 H); 8.26 (d, J = 8.6 Hz, 1 H); 8.46 (s, 1 H); 8.52(s, 1 H); 8.80 (d, J = 7.8 Hz, 1 H); 9.28 (s, 1 H) I-35 II-1 IIIb-372-{[4-(1H-Imidazol-1-yl)-2- 1.35 (d, J = 5.9 Hz, 6 H); 4.87 (spt, J =6.1 Hz, A (propan-2- 1 H); 7.07 (m, 2 H); 7.31 (d, J = 2.4 Hz, 471yloxy)phenyl]amino}-7- 1 H); 7.48 (t, J = 7.3 Hz, 1 H); 0.68phenylthieno[3,2- 7.58 (m, 3 H); 7.69 (d, J = 6.8 Hz, 2 H);d]pyrimidine-6- 7.71 (s, 1 H); 7.87 (broad s, 1 H); 8.10 (s, 1carboxamide H); 8.21 (s, 1 H); 8.46 (d, J = 8.8 Hz, 1 H); 9.30 (s, 1 H)I-36 II-1 IIIb-43 2-{[4-{Methyl[2-(pyrrolidin- (70-30 conformermixture): 1.27 (d, A 1-yl)ethyl]amino}-2- J = 6.4 Hz, 6 H); 1.74 (m, 4H); 2.66 (m, 531 (propan-2- 6 H); 2.87 (s, 3 H); 3.40 (t, J = 7.1 Hz, 20.71 yloxy)phenyl]amino}-7- H); 4.56 (m, 1 H); 6.21 (dd, J = 2.9 andphenylthieno[3,2- 8.8 Hz, 0.7 H); 6.26 (m, 0.3 H); 6.37 (d,d]pyrimidine-6- J = 2.4 Hz, 0.3 H); 6.40 (d, J = 2.9 Hz, 0.7 carboxamideH); 7.34 to 7.55 (m, 5 H); 7.65 (m, 3 H); 7.92 (d, J = 8.8 Hz, 1 H);9.11 (s, 1 H) I-37 II-5 IIIb-54 7-(2-Methoxyphenyl)-2- 1.19 (d, J = 5.9Hz, 6 H); 2.25 (s, 3 H); A {[6-(4-methylpiperazin-1- 2.43 (broad s, 4H); 3.42 (broad s, 4 H); 534 yl)-4-(propan-2- 3.69 (s, 3 H); 4.75 (spt,J = 5.9 Hz, 1 H); 0.46 yloxy)pyridin-3- 6.38 (s, 1 H); 6.74 (broad s, 1H); yl]amino}thieno[3,2- 7.05 (t, J = 7.5 Hz, 1 H); 7.13 (d, J = 8.1 Hz,1 d]pyrimidine-6- H); 7.38 (dd, J = 1.7 and 7.6 Hz, 1 H); carboxamide7.40 to 7.47 (m, 1 H); 7.69 (broad s, 1 H); 7.97 (s, 1 H); 8.27 (s, 1H); 9.09 (s, 1 H) I-38 II-5 IIIb-55 7-(2-Methoxyphenyl)-2- 1.25 (d, J =5.9 Hz, 6 H); 1.70 to 1.78 (m, A {[6-(1-methylpiperidin-4- 4 H); 1.88 to2.00 (m, 2 H); 2.19 (s, 3 533 yl)-4-(propan-2- H); 2.52 to 2.56 (m, 1H); 2.79 to 0.44 yloxy)pyridin-3- 2.92 (m, 2 H); 3.70 (s, 3 H); 4.78(quin, J = 6.4 Hz, yl]amino}thieno[3,2- 1 H); 6.80 (broad s, 1 H); 6.89(s, 1 d]pyrimidine-6- H); 7.07 (t, J = 7.3 Hz, 1 H); 7.15 (d,carboxamide J = 8.1 Hz, 1 H); 7.40 (dd, J = 1.2 and 7.6 Hz, 1 H); 7.43to 7.49 (m, 1 H); 7.72 (broad s, 1 H); 8.07 (s, 1 H); 8.82 (s, 1 H);9.19 (s, 1 H) I-39 II-11 IIIb-3 7-(5-Fluoro-2- 1.29 (d, J = 6.1 Hz, 6H); 1.57 to 1.75 (m, A methoxyphenyl)-2-{[4-(1- 4 H); 1.95 (m, 2 H);2.20 (s, 3 H); 550 methylpiperidin-4-yl)-2- 2.38 (m, 1 H); 2.86 (m, 2H); 3.68 (s, 3 H); 0.70 (propan-2- 4.67 (spt, J = 6.2 Hz, 1 H); 6.62(dd, yloxy)phenyl]amino}thieno[3, J = 1.5 and 8.3 Hz, 1 H); 6.88 (d, J =1.5 Hz, 2-d]pyrimidine-6- 1 H); 7.15 (dd, J = 4.6 and 9.3 Hz, 1carboxamide H); 7.25 (broad s, 1 H); 7.30 (td, J = 3.2 and 8.8 Hz, 1 H);7.37 (dd, J = 3.2 and 9.3 Hz, 1 H); 7.70 (broad s, 1 H); 7.92 (s, 1 H);8.16 (d, J = 8.3 Hz, 1 H); 9.22 (s, 1 H) I-40 II-9 IIIb-3 7-(3-Fluoro-2-1.27 (d, J = 6.1 Hz, 6 H); 1.56 to 1.73 (m, A methoxyphenyl)-2-{[4-(1- 4H); 1.94 (m, 2 H); 2.19 (s, 3 H); 550 methylpiperidin-4-yl)-2- 2.37 (m,1 H); 2.85 (m, 2 H); 3.65 (m, 3 H); 0.69 (propan-2- 4.65 (spt, J = 6.0Hz, 1 H); 6.60 (dd, yloxy)phenyl]amino}thieno[3, J = 1.5 and 8.8 Hz, 1H); 6.87 (d, J = 1.0 Hz, 2-d]pyrimidine-6- 1 H); 7.26 (m, 3 H); 7.39(ddd, carboxamide J = 2.3 and 7.7 and 12.0 Hz, 1 H); 7.76 (broad s, 1H); 7.92 (s, 1 H); 8.06 (d, J = 8.3 Hz, 1 H); 9.23 (s, 1 H) I-41 II-24IIIb-3 2-{[4-(1-Methylpiperidin-4- (70/30 rotamer mixture): 1.25 (m, 6H); A yl)-2-(propan-2- 1.56 to 1.71 (m, 4 H); 1.93 (m, 2 H); 564yloxy)phenyl]amino}-7-[2- 2.18 (s, 3 H); 2.35 (m, 1.9 H); 2.54 (s, 0.60(methylsulfinyl)phenyl]thieno[3, 2.1 H); 2.84 (d, J = 11.0 Hz, 2 H);2-d]pyrimidine-6- 4.62 (m, 1 H); 6.47 (d, J = 9.3 Hz, 0.7 H);carboxamide 6.55 (d, J = 8.6 Hz, 0.3 H); 6.84 (s, 1 H); 7.24 (broad s, 1H); 7.37 (d, J = 7.1 Hz, 0.7 H); 7.46 (d, J = 7.1 Hz, 0.3 H); 7.64 (t, J= 7.5 Hz, 0.7 H); 7.70 (d, J = 7.8 Hz, 0.3H); 7.75 to 7.94 (m, 3.7 H);8.06 (m, 1.3 H); 9.92 (m, 1 H) I-42 II-5 IIIb-34 2-({4-[3- 1.26 (d, J =6.1 Hz, 6 H); 1.79 (m, 1 H); A (Dimethylamino)pyrrolidin- 2.11 (m, 1 H);2.21 (s, 6 H); 547 1-yl]-2-(propan-2- 2.47 (masked m, 1 H); 2.78 (quin,J = 7.8 Hz, 0.67 yloxy)phenyl}amino)-7-(2- 1 H); 3.00 (t, J = 8.3 Hz, 1H); 3.19 (m, 1 methoxyphenyl)thieno[3,2- H); 3.38 (t, J = 8.1 Hz, 1 H);3.70 (s, 3 H); d]pyrimidine-6- 4.62 (spt, J = 6.0 Hz, 1 H); 5.94 (dd,carboxamide J = 1.8 and 8.4 Hz, 1 H); 6.21 (d, J = 2.4 Hz, 1 H); 6.82(broad s, 1 H); 7.11 (t, J = 7.1 Hz, 1 H); 7.17 (d, J = 8.3 Hz, 1 H);7.47 (m, 2 H); 7.68 (m, 2 H); 7.83 (d, J = 8.6 Hz, 1 H); 9.11 (s, 1 H)I-43 II-5 IIIb-43 7-(2-Methoxyphenyl)-2- 1.26 (d, J = 6.1 Hz, 6 H); 1.68(m, 4 H); A {[4-{methyl[2-(pyrrolidin-1- 2.48 (masked m, 4 H); 2.54 (m,2 H); 561 yl)ethyl]amino}-2-(propan- 2.86 (s, 3 H); 3.38 (t, J = 7.5 Hz,2 H); 0.70 2- 3.70 (s, 3 H); 4.58 (spt, J = 6.1 Hz, 1 H);yloxy)phenyl]amino}thieno[3, 6.10 (dd, J = 2.4 and 8.6 Hz, 1 H);2-d]pyrimidine-6- 6.35 (d, J = 2.2 Hz, 1 H); 6.84 (broad s, 1 H);carboxamide 7.10 (t, J = 7.5 Hz, 1 H); 7.16 (d, J = 8.3 Hz, 1 H); 7.44(m, 2 H); 7.70 (m, 2 H); 7.83 (d, J = 8.6 Hz, 1 H); 9.12 (s, 1 H) I-44II-14 IIIb-3 7-(2-Fluoro-3- 1.29 (d, J = 6.1 Hz, 6 H); 1.66 (m, 4 H); Amethoxyphenyl)-2-{[4-(1- 1.95 (m, 2 H); 2.20 (s, 3 H); 2.37 (m, 1 550methylpiperidin-4-yl)-2- H); 2.86 (m, 2 H); 3.93 (s, 3 H); 0.69(propan-2- 4.67 (spt, J = 6.0 Hz, 1 H); 6.61 (dd, J = 1.6yloxy)phenyl]amino}thieno[3, and 7.9 Hz, 1 H); 6.88 (d, J = 2.0 Hz, 12-d]pyrimidine-6- H); 7.13 (m, 1 H); 7.28 (m, 2 H); carboxamide 7.53(broad s, 1 H); 7.77 (broad s, 1 H); 7.93 (s, 1 H); 8.15 (d, J = 8.3 Hz,1 H); 9.25 (s, 1 H) I-45 II-5 IIIb-19 2-{[4-(1-Ethylpiperidin-3- 1.00(t, J = 7.1 Hz, 3 H); 1.29 (d, J = 6.1 Hz, A yl)-2-(propan-2- 6 H); 1.40(m, 1 H); 1.51 (m, 1 H); 546 yloxy)phenyl]amino}-7-(2- 1.73 (m, 2 H);1.89 (m, 2 H); 2.34 (q, 0.72 methoxyphenyl)thieno[3,2- J = 7.1 Hz, 2 H);2.65 (m, 1 H); 2.85 (t, d]pyrimidine-6- J = 11.1 Hz, 2 H); 3.70 (s, 3H); 4.67 (spt, carboxamide J = 6.0 Hz, 1 H); 6.61 (d, J = 9.0 Hz, 1 H);6.85 to 6.94 (m, 2 H); 7.13 (t, J = 7.5 Hz, 1 H); 7.20 (d, J = 8.1 Hz, 1H); 7.48 (m, 2 H); 7.73 (broad s, 1 H); 7.87 (s, 1 H); 8.12 (d, J = 8.1Hz, 1 H); 9.21 (s, 1 H) I-46 II-16 IIIb-3 7-(2-Fluorophenyl)-2-{[4- 1.29(d, J = 5.9 Hz, 6 H); 1.65 (m, 4 H); A (1-methylpiperidin-4-yl)-2- 1.93(m, 2 H); 2.19 (s, 3 H); 2.38 (m, 1 520 (propan-2- H); 2.85 (d, J = 11.2Hz, 2 H); 4.67 (spt, 0.69 yloxy)phenyl]amino}thieno[3, J = 5.9 Hz, 1 H);6.64 (d, J = 8.8 Hz, 1 H); 2-d]pyrimidine-6- 6.88 (s, 1 H); 7.36 (m, 2H); 7.58 (m, 3 carboxamide H); 7.78 (broad s, 1 H); 7.94 (s, 1 H); 8.15(d, J = 8.3 Hz, 1 H); 9.26 (s, 1 H) I-47 II-32 IIIb-32-{[4-(1-Methylpiperidin-4- 1.27 (d, J = 5.9 Hz, 6 H); 1.71 (m, 4 H); Ayl)-2-(propan-2- 1.96 (m, 2 H); 2.20 (s, 3 H); 2.43 (m, 1 491yloxy)phenyl]amino}-7- H); 2.87 (m, 2 H); 4.66 (spt, J = 6.0 Hz, 1 0.56(1H-pyrrol-2-yl)thieno[3,2- H); 6.20 (q, J = 2.9 Hz, 1 H); 6.83 (dd,d]pyrimidine-6- J = 1.7 and 8.1 Hz, 1 H); 6.94 (m, 3 H); carboxamide7.95 to 8.04 (m, 3 H); 8.33 (s, 1 H); 9.19 (s, 1 H); 11.74 (broad s, 1H) I-48 II-26 IIIb-3 7-[2-Fluoro-5- 1.30 (d, J = 5.9 Hz, 6 H); 1.56 to1.74 (m, A (hydroxymethyl)phenyl]-2- 4 H); 1.95 (m, 2 H); 2.19 (s, 3 H);550 {[4-(1-methylpiperidin-4- 2.36 (m, 1 H); 2.85 (d, J = 11.5 Hz, 2 H);0.64 yl)-2-(propan-2- 4.59 (d, J = 5.6 Hz, 2 H); 4.68 (spt, J = 6.1 Hz,yloxy)phenyl]amino}thieno[3, 1 H); 5.30 (t, J = 5.9 Hz, 1 H); 6.68 (dd,2-d]pyrimidine-6- J = 1.0 and 7.6 Hz, 1 H); 6.88 (d, J = 1.5 Hz,carboxamide 1 H); 7.30 (dd, J = 8.6 and 10.0 Hz, 1 H); 7.43 to 7.53 (m,1 H); 7.53 to 7.61 (m, 2 H); 7.75 (broad s, 1 H); 7.93 (s, 1 H); 8.17(d, J = 8.3 Hz, 1 H); 9.26 (s, 1 H) I-49 II-5 IIIb-8 2-{[4-(5-Methoxy-1-1.31 (d, J = 6.4 Hz, 6 H); 2.30 (broad s, 3 C methyl-1,2,3,6- H); 2.39(m, 2 H); 2.47 (masked m, 2 560 tetrahydropyridin-4-yl)-2- H); 3.02(broad s, 2 H); 3.43 (broad s, 3 3.58 (propan-2- H); 3.71 (broad s, 3H); 4.62 (s, 1 H); yloxy)phenyl]amino}-7-(2- 6.76 (d, J = 9.3 Hz, 1 H);6.91 (broad s, 1 methoxyphenyl)thieno[3,2- H); 7.10 (m, 2 H); 7.19 (dd,J = 0.6 and d]pyrimidine-6- 7.9 Hz, 1 H); 7.46 (m, 2 H); 7.74 (broadcarboxamide s, 1 H); 7.91 (d, J = 0.7 Hz, 1 H); 8.18 (d, J = 7.8 Hz, 1H); 9.23 (broad s, 1 H) I-50 II-10 IIIb-25 7-(4-Fluoro-2- 1.26 (d, J =5.9 Hz, 6 H); 2.22 (s, 3 H); C methoxyphenyl)-2-{[4-(4- 2.45 (t, J = 4.9Hz, 4 H); 3.06 (t, J = 4.6 Hz, 551 methylpiperazin-1-yl)-2- 4 H); 3.71(s, 3 H); 4.65 (spt, J = 6.0 Hz, 3.39 (propan-2- 1 H); 6.36 (dd, J = 2.6and 8.9 Hz, 1 yloxy)phenyl]amino}thieno[3, H); 6.62 (d, J = 2.4 Hz, 1H); 6.95 (td, 2-d]pyrimidine-6- J = 2.6 and 8.5 Hz, 1 H); 7.04 (broad s,1 carboxamide H); 7.08 (dd, J = 2.4 and 11.5 Hz, 1 H); 7.48 (dd, J = 7.0and 8.4 Hz, 1 H); 7.69 (broad s, 1 H); 7.78 (s, 1 H); 7.95 (d, J = 9.0Hz, 1 H); 9.15 (s, 1 H) I-51 II-5 IIIb-37 2-{[4-(1H-Imidazol-1-yl)-2-1.34 (d, J = 6.0 Hz, 6 H); 3.72 (s, 3 H); C (propan-2- 4.87 (m, 1 H);6.94 (broad s, 1 H); 501 yloxy)phenyl]amino}-7-(2- 6.98 (dd, J = 2.5 and8.7 Hz, 1 H); 7.08 (t, 3.46 methoxyphenyl)thieno[3,2- J = 1.2 Hz, 1 H);7.16 (m, 1 H); 7.21 (d, d]pyrimidine-6- J = 7.8 Hz, 1 H); 7.29 (d, J =2.5 Hz, 1 H); carboxamide 7.48 (m, 2 H); 7.69 (t, J = 1.4 Hz, 1 H); 7.76(broad s, 1 H); 8.03 (s, 1 H); 8.18 (t, J = 1.2 Hz, 1 H); 8.35 (d, J =8.7 Hz, 1 H); 9.27 (s, 1 H) I-52 II-5 IIIb-58 2-Methylpropan-2-yl 4-[5-1.23 (d, J = 6.4 Hz, 6 H); 1.32 (m, 2 H); A {[6-carbamoyl-7-(2- 1.45 (s,9 H); 1.70 (m, 2 H); 2.62 (m, 1 592 methoxyphenyl)thieno[3,2- H); 2.74to 2.89 (m, 2 H); 3.66 (s, 3 H); 0.99 d]pyrimidin-2-yl]amino}- 3.99 (m,2 H); 4.54 (m, 1 H); 6.03 (s, 1 1-(propan-2-yl)-1H- H); 6.72 (broad s, 1H); 7.05 (t, J = 7.0 Hz, pyrazol-3-yl]piperidine-1- 1 H); 7.13 (d, J =7.6 Hz, 1 H); carboxylate 7.37 (dd, J = 1.7 and 7.6 Hz, 1 H); 7.45 (ddd,J = 1.7 and 7.2 and 8.5 Hz, 1 H); 7.75 (broad s, 1 H); 9.22 (s, 1 H);9.44 (broad s, 1 H) I-53 II-5 IIIb-9 7-(2-Methoxyphenyl)-2- 1.10 (m, 6H); 1.23 (m, 6 H); 1.29 (m, 2 A {[2-(propan-2-yloxy)-4- H); 1.30 (d, J =6.1 Hz, 6 H); 1.59 (m, 2 574 (2,2,6,6- H); 2.96 (m, 1 H); 3.71 (s, 3 H);0.79 tetramethylpiperidin-4- 4.68 (spt, J = 6.1 Hz, 1 H); 6.60 (dd, J =1.2 yl)phenyl]amino}thieno[3, and 8.3 Hz, 1 H); 6.89 (m, 2 H);2-d]pyrimidine-6- 7.14 (td, J = 1.0 and 7.5 Hz, 1 H); 7.20 (d,carboxamide J = 7.8 Hz, 1 H); 7.45 (m, 2 H); 7.73 (broad s, 1 H); 7.88(s, 1 H); 8.14 (d, J = 8.3 Hz, 1 H); 9.22 (s, 1 H) I-54 II-5 IIIb-112-{[4-(2,6- (60/40 diastereoisomer mixture) 0.90 to ADimethylpiperidin-4-yl)-2- 1.12 (m, 8.6 H); 1.29 (dd, J = 2.6 and 6.0Hz, 546 (propan-2- 6 H); 1.41 (m, 0.4 H); 1.63 (m, 0.6 0.75yloxy)phenyl]amino}-7-(2- H); 1.99 (d, J = 13.9 Hz, 0.4 H); 2.56 (s,methoxyphenyl)thieno[3,2- 1 H); 2.64 to 2.82 (m, 2 H); 3.68 tod]pyrimidine-6- 3.73 (m, 3 H); 4.53 to 4.72 (m, 1 H); carboxamide 6.57(dd, J = 1.2 and 7.6 Hz, 0.6 H); 6.70 (d, J = 8.6 Hz, 0.4 H); 6.82 to6.96 (m, 2 H); 7.08 to 7.22 (m, 2 H); 7.42 to 7.56 (m, 2 H); 7.73 (broads, 1 H); 7.87 (d, J = 10.5 Hz, 1 H); 8.03 to 8.16 (m, 1 H); 9.21 (s, 1H) I-55 II-5 IIIb-12 2-{[4-(2-Ethylpiperidin-4- (50/50 diastereoisomermixture) 0.88 (t, C yl)-2-(propan-2- J = 7.4 Hz, 3 H); 1.06 to 1.83 (m,12 H); 546 yloxy)phenyl]amino}-7-(2- 2.35 to 2.43 (m, 0.5 H); 2.52 to2.86 (m, 3.72 and methoxyphenyl)thieno[3,2- 5 H); 3.04 (m, 0.5 H); 3.70(s, 3 H); 3.75 d]pyrimidine-6- 4.66 (spt, J = 6.0 Hz, 1 H); 6.57 (m, 1H); carboxamide 6.86 (d, J = 8.8 Hz, 1 H); 6.91 (broad s, 1 H); 7.13 (t,J = 7.4 Hz, 1 H); 7.20 (d, J = 8.2 Hz, 1 H); 7.48 (m, 2 H); 7.74 (broads, 1 H); 7.87 (s, 1 H); 8.13 (d, J = 8.5 Hz, 1 H); 9.21 (s, 1 H) I-56II-5 IIIb-4 7-(2-Methoxyphenyl)-2- 1.30 (d, J = 6.1 Hz, 6 H); 1.49 (qd,J = 3.9 A {[4-(piperidin-4-yl)-2- and 12.3 Hz, 2 H); 1.65 (m, 2 H); 518(propan-2- 2.48 (masked m, 1 H); 2.59 (m, 2 H); 0.68yloxy)phenyl]amino}thieno[3, 3.03 (m, 2 H); 3.70 (s, 3 H); 4.66 (spt, J= 6.1 Hz, 2-d]pyrimidine-6- 2 H); 6.58 (dd, J = 1.7 and 8.6 Hz, 1carboxamide H); 6.85 (d, J = 1.2 Hz, 1 H); 6.90 (broad s, 1 H); 7.13(td, J = 1.1 and 7.4 Hz, 1 H); 7.20 (d, J = 7.6 Hz, 1 H); 7.48 (m, 2 H);7.74 (broad s, 1 H); 7.87 (s, 1 H); 8.14 (d, J = 8.3 Hz, 1 H); 9.21 (s,1 H) I-57 II-10 IIIb-3 7-(4-Fluoro-2- 1.29 (d, J = 6.0 Hz, 6 H); 1.54 to1.77 (m, A methoxyphenyl)-2-{[4-(1- 4 H); 1.97 (td, J = 3.4 and 11.2 Hz,2 H); 550 methylpiperidin-4-yl)-2- 2.20 (s, 3 H); 2.39 (m, 1 H); 2.87(d, 0.68 (propan-2- J = 11.8 Hz, 2 H); 3.71 (s, 3 H); 4.67 (spt,yloxy)phenyl]amino}thieno[3, J = 6.1 Hz, 1 H); 6.66 (dd, J = 1.7 and 8.4Hz, 2-d]pyrimidine-6- 1 H); 6.88 (d, J = 1.7 Hz, 1 H); carboxamide 6.96(td, J = 2.5 and 8.5 Hz, 1 H); 7.10 (, 1 H); 7.10 (dd, J = 2.6 and 11.6Hz, 1 H); 7.49 (dd, J = 7.1 and 8.3 Hz, 1 H); 7.72 (broad s, 1 H); 7.88(s, 1 H); 8.13 (d, J = 8.4 Hz, 1 H); 9.21 (s, 1 H) I-58 II-5 IIIb-272-{[4-(3,5- 1.13 (m, 6 H); 1.27 (d, J = 6.1 Hz, 6 H); ADimethylpiperazin-1-yl)-2- 2.19 (m, 2 H); 2.89 to 3.13 (m, 2 H); 547(propan-2- 3.52 (broad s, 2 H); 3.70 (s, 3 H); 0.69yloxy)phenyl]amino}-7-(2- 4.66 (spt, J = 6.1 Hz, 1 H); 6.32 (d, J = 9.0Hz, methoxyphenyl)thieno[3,2- 1 H); 6.64 (broad s, 1 H); 6.86 (broad s,d]pyrimidine-6- 1 H); 7.13 (t, J = 7.3 Hz, 1 H); 7.18 (d, carboxamide J= 8.3 Hz, 1 H); 7.47 (m, 2 H); 7.71 (broad s, 1 H); 7.78 (s, 1 H); 7.96(d, J = 8.6 Hz, 1 H); 9.16 (s, 1 H) I-59 II-5 IIIb-287-(2-Methoxyphenyl)-2- 1.06 (s, 3 H); 1.08 (s, 3 H); 1.26 (d, A{[2-(propan-2-yloxy)-4- J = 5.9 Hz, 6 H); 2.19 (s, 3 H); 2.29 (m, 4 561(3,4,5-trimethylpiperazin- H); 3.43 (d, J = 10.8 Hz, 2 H); 3.70 (s, 30.70 1- H); 4.66 (spt, J = 6.0 Hz, 1 H); 6.29 (dd,yl)phenyl]amino}thieno[3, J = 2.3 and 8.7 Hz, 1 H); 6.61 (dd, J = 0.52-d]pyrimidine-6- and 2.2 Hz, 1 H); 6.85 (broad s, 1 H); carboxamide7.13 (t, J = 7.5 Hz, 1 H); 7.18 (d, J = 7.8 Hz, 1 H); 7.47 (m, 2 H);7.71 (broad s, 1 H); 7.77 (s, 1 H); 7.93 (d, J = 8.8 Hz, 1 H); 9.15 (s,1 H) I-60 II-5 IIIb-44 2-({4-[(8aR)- 1.26 (d, J = 6.1 Hz, 6 H); 1.37 (m,1 H); A Hexahydropyrrolo[1,2- 1.71 (m, 2 H); 1.83 (m, 1 H); 2.06 (m, 2559 a]pyrazin-2(1H)-yl]-2- H); 2.23 (td, J = 3.2 and 11.1 Hz, 1 H); 0.69(propan-2- 2.34 (m, 1 H); 2.67 (td, J = 3.2 and 11.5 Hz,yloxy)phenyl}amino)-7-(2- 1 H); 3.00 (m, 2 H); 3.51 (d, J = 11.2 Hz,methoxyphenyl)thieno[3,2- 1 H); 3.66 (d, J = 10.5 Hz, 1 H);d]pyrimidine-6- 3.70 (s, 3 H); 4.65 (spt, J = 6.1 Hz, 1 H); carboxamide6.31 (dd, J = 2.4 and 9.0 Hz, 1 H); 6.63 (d, J = 2.7 Hz, 1 H); 6.86(broad s, 1 H); 7.13 (t, J = 7.5 Hz, 1 H); 7.19 (d, J = 7.6 Hz, 1 H);7.46 (m, 2 H); 7.71 (broad s, 1 H); 7.76 (s, 1 H); 7.96 (d, J = 9.0 Hz,1 H); 9.15 (s, 1 H) I-61 II-5 IIIb-58 7-(2-Methoxyphenyl)-2- 1.23 (d, J= 6.4 Hz, 6 H); 1.68 (m, 2 H); A {[3-(piperidin-4-yl)-1- 1.97 (m, 2 H);2.79 (m, 1 H); 2.98 (m, 2 492 (propan-2-yl)-1H-pyrazol- H); 3.30 (m, 2H); 3.67 (s, 3 H); 0.52 5-yl]amino}thieno[3,2- 4.52 (spt, J = 6.0 Hz, 1H); 6.01 (s, 1 H); d]pyrimidine-6- 6.73 (broad s, 1 H); 7.09 (t, J = 7.3Hz, 1 H); carboxamide 7.17 (d, J = 8.3 Hz, 1 H); 7.35 (dd, J = 1.2 and7.6 Hz, 1 H); 7.47 (t, J = 7.3 Hz, 1 H); 7.78 (broad s, 1 H); 8.49 (m, 1H); 8.83 (m, 1 H); 9.22 (s, 1 H); 9.44 (s, 1 H) I-62 II-5 IIIb-192-({4-[(3R)-1- 1.00 (t, J = 7.2 Hz, 3 H); 1.29 (d, J = 5.9 Hz, AEthylpiperidin-3-yl]-2- 6 H); 1.40 (m, 1 H); 1.55 (ddd, 546 (propan-2- J= 3.8 and 3.9 and 12.3 Hz, 1 H); 0.73 yloxy)phenyl}amino)-7-(2- 1.72 (m,2 H); 1.89 (m, 2 H); 2.34 (q, J = 7.1 Hz, methoxyphenyl)thieno[3,2- 2H); 2.64 (m, 1 H); 2.84 (m, 2 H); d]pyrimidine-6- 3.70 (s, 3 H); 4.67(spt, J = 6.1 Hz, 1 H); carboxamide 6.61 (dd, J = 1.7 and 8.6 Hz, 1 H);6.90 (broad s, 1 H); 6.90 (d, J = 2.0 Hz, 1 H); 7.13 (td, J = 1.0 and7.5 Hz, 1 H); 7.20 (d, J = 7.6 Hz, 1 H); 7.47 (m, 2 H); 7.73 (broad s, 1H); 7.87 (s, 1 H); 8.12 (d, J = 8.3 Hz, 1 H); 9.21 (s, 1 H) I-63 II-5IIIb-19 2-({4-[(3S)-1- 1.00 (t, J = 7.1 Hz, 3 H); 1.29 (d, J = 5.9 Hz, AEthylpiperidin-3-yl]-2- 6 H); 1.40 (qd, J = 3.7 and 12.1 Hz, 1 546(propan-2- H); 1.53 (m, 1 H); 1.72 (m, 2 H); 0.73yloxy)phenyl}amino)-7-(2- 1.90 (m, 2 H); 2.34 (q, J = 7.3 Hz, 2 H);methoxyphenyl)thieno[3,2- 2.64 (m, 1 H); 2.84 (m, 2 H); 3.70 (s, 3 H);d]pyrimidine-6- 4.67 (spt, J = 6.0 Hz, 1 H); 6.61 (dd, carboxamide J =1.5 and 8.1 Hz, 1 H); 6.90 (broad s, 1 H); 6.90 (d, J = 1.5 Hz, 1 H);7.13 (td, J = 1.1 and 7.4 Hz, 1 H); 7.20 (d, J = 7.6 Hz, 1 H); 7.49 (m,2 H); 7.73 (broad s, 1 H); 7.87 (s, 1 H); 8.12 (d, J = 8.3 Hz, 1 H);9.21 (s, 1 H) I-64 II-27 IIIb-3 2-{[4-(1-Methylpiperidin-4- 1.29 (d, J =5.9 Hz, 6 H); 1.68 (m, 4 H); A yl)-2-(propan-2- 1.96 (m, 2 H); 2.19 (s,3 H); 2.41 (m, 1 508 yloxy)phenyl]amino}-7- H); 2.86 (m, 2 H); 4.68(spt, J = 6.1 Hz, 1 0.68 (thiophen-3-yl)thieno[3,2- H); 6.76 (dt, J =1.0 and 8.3 Hz, 1 H); d]pyrimidine-6- 6.92 (d, J = 2.0 Hz, 1 H); 7.53(dd, J = 1.3 carboxamide and 5.0 Hz, 1 H); 7.70 (dd, J = 2.9 and 5.1 Hz,1 H); 7.78 (broad s, 1 H); 7.92 (broad s, 1 H); 8.02 (m, 2 H); 8.20 (d,J = 8.3 Hz, 1 H); 9.22 (s, 1 H) I-65 II-33 IIIb-3 7-(5-Fluoro-2- 1.27(m, 6 H); 1.55 to 1.83 (m, 4 H); A methoxypyridin-4-yl)-2- 1.92 to 2.35(m, 6 H); 2.83 to 3.02 (m, 2 551 {[4-(1-methylpiperidin-4- H); 3.94(broad s, 3 H); 4.66 (m, 1 H); 0.67 yl)-2-(propan-2- 6.67 (d, J = 8.6Hz, 1 H); 6.90 (broad s, 1 yloxy)phenyl]amino}thieno[3, H); 7.11 (m, 1H); 7.80 (m, 2 H); 2-d]pyrimidine-6- 8.04 (broad s, 1 H); 8.12 (d, J =8.3 Hz, 1 H); carboxamide 8.26 (broad s, 1 H); 9.28 (broad s, 1 H) I-66II-5 IIIb-15 7-(2-Methoxyphenyl)-2- 0.89 (t, J = 7.3 Hz, 6 H); 1.15 (m,1 H); A ({2-(propan-2-yloxy)-4- 1.29 (d, J = 5.9 Hz, 6 H); 1.39 to 1.72(m, 560 [(2R,4S)-2-(propan-2- 4 H); 2.35 (m, 1 H); 2.53 (d, J = 6.6 Hz,1 0.77 yl)piperidin-4- H); 2.65 (m, 1 H); 3.09 (m, 1 H); 3.70 (s,yl]phenyl}amino)thieno[3, 3 H); 4.66 (spt, J = 6.0 Hz, 1 H);2-d]pyrimidine-6- 6.59 (dd, J = 1.6 and 8.2 Hz, 1 H); 6.85 (d,carboxamide J = 1.5 Hz, 1 H); 6.90 (broad s, 1 H); 7.13 (t, J = 7.5 Hz,1 H); 7.19 (d, J = 7.8 Hz, 1 H); 7.49 (m, 2 H); 7.73 (broad s, 1 H);7.87 (s, 1 H); 8.12 (d, J = 8.1 Hz, 1 H); 9.21 (s, 1 H) I-67 II-5IIIb-15 7-(2-Methoxyphenyl)-2- 0.86 (d, J = 6.6 Hz, 3 H); 0.92 (d, J =6.6 Hz, A ({2-(propan-2-yloxy)-4- 3 H); 1.30 (d, J = 6.1 Hz, 6 H); 1.55560 [(2R,4R)-2-(propan-2- to 1.82 (m, 4 H); 1.94 (m, 1 H); 2.38 (m, 0.77yl)piperidin-4- 1 H); 2.61 to 2.91 (m, 3 H); 3.70 (s, 3yl]phenyl}amino)thieno[3, H); 4.64 (spt, J = 6.0 Hz, 1 H); 6.62 (d,2-d]pyrimidine-6- J = 8.3 Hz, 1 H); 6.87 (s, 1 H); carboxamide 6.90(broad s, 1 H); 7.13 (t, J = 7.5 Hz, 1 H); 7.19 (d, J = 8.3 Hz, 1 H);7.49 (m, 2 H); 7.73 (broad s, 1 H); 7.87 (s, 1 H); 8.13 (d, J = 8.3 Hz,1 H); 9.21 (s, 1 H) I-68 II-2 IIIb-3 7-(2-Chlorophenyl)-2-{[4- 1.28 (d,J = 6.1 Hz, 6 H); 1.63 (m, 4 H); A (1-methylpiperidin-4-yl)-2- 1.93 (m,2 H); 2.19 (s, 3 H); 2.36 (m, 1 536 (propan-2- H); 2.84 (m, 2 H); 4.66(spt, J = 6.1 Hz, 1 0.71 yloxy)phenyl]amino}thieno[3, H); 6.54 (dd, J =2.0 and 8.3 Hz, 1 H); 2-d]pyrimidine-6- 6.86 (d, J = 2.0 Hz, 1 H); 7.19(broad s, 1 carboxamide H); 7.52 (m, 3 H); 7.63 (m, 1 H); 7.79 (broad s,1 H); 7.91 (s, 1 H); 8.01 (d, J = 8.3 Hz, 1 H); 9.25 (s, 1 H) I-69 II-31IIIb-44 2-({4-[(8aR)- 1.26 (d, J = 5.9 Hz, 6 H); 1.32 to 1.58 (m, AHexahydropyrrolo[1,2- 1 H); 1.65 to 1.76 (m, 1 H); 1.83 (m, 1 560a]pyrazin-2(1H)-yl]-2- H); 2.06 (m, 2 H); 2.23 (m, 1 H); 0.64 (propan-2-2.34 (m, 2 H); 2.67 (m, 1 H); 3.02 (m, 2 H); yloxy)phenyl}amino)-7-(2-3.53 (d, J = 11.7 Hz, 1 H); 3.68 (d, methoxypyridin-3- J = 11.7 Hz, 1H); 3.80 (s, 3 H); 4.66 (spt, yl)thieno[3,2-d]pyrimidine- J = 6.0 Hz, 1H); 6.35 (d, J = 8.8 Hz, 1 H); 6-carboxamide 6.64 (d, J = 1.5 Hz, 1 H);7.17 (dd, J = 5.1 and 7.6 Hz, 1 H); 7.46 (broad s, 1 H); 7.68 (broad s,1 H); 7.82 (s, 1 H); 7.92 (m, 2 H); 8.26 (d, J = 2.9 Hz, 1 H); 9.18 (s,1 H) I-70 II-5 IIIb-58 2-{[3-(1-Ethylpiperidin-4- 1.04 (t, J = 7.1 Hz, 3H); 1.22 (d, J = 6.8 Hz, A yl)-1-(propan-2-yl)-1H- 6 H); 1.48 (m, 2 H);1.73 (m, 2 H); 520 pyrazol-5-yl]amino}-7-(2- 1.91 (m, 2 H); 2.37 (m, 3H); 2.91 (d, 0.53 methoxyphenyl)thieno[3,2- J = 11.7 Hz, 2 H); 3.66 (s,3 H); 4.48 (spt, d]pyrimidine-6- J = 6.0 Hz, 1 H); 6.00 (s, 1 H);carboxamide 6.71 (broad s, 1 H); 7.08 (t, J = 7.6 Hz, 1 H); 7.14 (d, J =8.3 Hz, 1 H); 7.36 (d, J = 7.3 Hz, 1 H); 7.43 (t, J = 7.8 Hz, 1 H); 7.75(broad s, 1 H); 9.21 (s, 1 H); 9.34 (s, 1 H) I-71 II-3 IIIb-37-(3-Chlorophenyl)-2-{[4- 1.30 (d, J = 5.9 Hz, 6 H); 1.67 (m, 4 H); A(1-methylpiperidin-4-yl)-2- 1.95 (td, J = 2.3 and 11.8 Hz, 2 H); 536(propan-2- 2.19 (s, 3 H); 2.40 (m, 1 H); 2.86 (m, 2 H); 0.73yloxy)phenyl]amino}thieno[3, 4.69 (spt, J = 6.1 Hz, 1 H); 6.76 (dd,2-d]pyrimidine-6- J = 2.0 and 8.3 Hz, 1 H); 6.91 (d, J = 1.5 Hz,carboxamide 1 H); 7.55 (m, 3 H); 7.81 (d, J = 1.5 Hz, 1 H); 7.84 (broads, 1 H); 7.88 (broad s, 1 H); 8.00 (s, 1 H); 8.24 (d, J = 8.3 Hz, 1 H);9.26 (s, 1 H) I-72 II-21 IIIb-3 7-(2-Methylphenyl)-2-{[4- 1.27 (d, J =6.1 Hz, 6 H); 1.55 to 1.71 (m, A (1-methylpiperidin-4-yl)-2- 4 H); 1.93(m, 2 H); 2.11 (s, 3 H); 516 (propan-2- 2.19 (s, 3 H); 2.36 (m, 1 H);2.85 (d, J = 11.7 Hz, 0.73 yloxy)phenyl]amino}thieno[3, 2 H); 4.64 (spt,J = 6.0 Hz, 1 H); 2-d]pyrimidine-6- 6.52 (dd, J = 1.5 and 8.3 Hz, 1 H);6.63 (broad carboxamide s, 1 H); 6.86 (d, J = 1.0 Hz, 1 H); 7.33 (m, 2H); 7.44 (m, 2 H); 7.84 (broad s, 1 H); 7.90 (s, 1 H); 7.95 (d, J = 8.3Hz, 1 H); 9.24 (s, 1 H) I-73 II-34 IIIb-3 2-{[4-(1-Methylpiperidin-4-1.29 (d, J = 5.9 Hz, 6 H); 1.72 (m, 4 H); A yl)-2-(propan-2- 1.96 (t, J= 10.5 Hz, 2 H); 2.20 (s, 3 H); 506 yloxy)phenyl]amino}-7-(1- 2.45 (m, 1H); 2.87 (d, J = 11.5 Hz, 2 H); 0.60 methyl-1H-pyrazol-4- 3.92 (s, 3 H);4.69 (m, 1 H); 6.84 (d, yl)thieno[3,2-d]pyrimidine- J = 7.8 Hz, 1 H);6.95 (s, 1 H); 6-carboxamide 7.90 (broad s, 1 H); 7.97 (m, 2 H); 8.08(s, 1 H); 8.14 (d, J = 8.3 Hz, 1 H); 8.32 (s, 1 H); 9.18 (s, 1 H) I-74II-8 IIIb-3 7-(2,5-Dimethoxyphenyl)- 1.29 (d, J = 5.9 Hz, 6 H); 1.53 to1.75 (m, A 2-{[4-(1-methylpiperidin-4- 4 H); 1.94 (m, 2 H); 2.19 (s, 3H); 562 yl)-2-(propan-2- 2.37 (m, 1 H); 2.85 (d, J = 11.2 Hz, 2 H); 0.69yloxy)phenyl]amino}thieno[3, 3.65 (s, 3 H); 3.77 (s, 3 H); 4.67 (spt, J= 5.9 Hz, 2-d]pyrimidine-6- 1 H); 6.59 (d, J = 8.3 Hz, 1 H); carboxamide6.88 (s, 1 H); 6.97 (broad s, 1 H); 7.07 (m, 3 H); 7.72 (broad s, 1 H);7.88 (s, 1 H); 8.18 (d, J = 8.3 Hz, 1 H); 9.21 (s, 1 H) I-75 II-18IIIb-3 7-[2- 1.27 (d, J = 6.1 Hz, 6 H); 1.66 to 1.90 (m, A(Difluoromethoxy)phenyl]- 4 H); 2.38 to 2.57 (partially masked m, 6 5682-{[4-(1-methylpiperidin-4- H); 3.20 (m, 2 H); 4.62 (m, 1 H); 0.70yl)-2-(propan-2- 6.61 (dd, J = 1.3 and 8.5 Hz, 1 H); 6.86 (d,yloxy)phenyl]amino}thieno[3, J = 1.3 Hz, 1 H); 6.92 (t, J = 74.1 Hz, 1H); 2-d]pyrimidine-6- 7.32 (d, J = 7.8 Hz, 1 H); 7.35 (broad s, 1carboxamide H); 7.40 (t, J = 7.8 Hz, 1 H); 7.52 to 7.59 (m, 2 H); 7.77(broad s, 1 H); 8.01 (m, 2 H); 9.24 (s, 1 H) I-76 II-35 IIIb-32-{[4-(1-Methylpiperidin-4- 1.30 (d, J = 5.9 Hz, 6 H); 1.74 (m, 4 H); Ayl)-2-(propan-2- 2.03 (t, J = 10.5 Hz, 2 H); 2.24 (s, 3 H); 492yloxy)phenyl]amino}-7- 2.44 (m, 1 H); 2.92 (m, 2 H); 4.68 (spt, 0.59(1H-pyrazol-4- J = 6.1 Hz, 1 H); 6.81 (dd, J = 1.5 and 8.3 Hz,yl)thieno[3,2-d]pyrimidine- 1 H); 6.94 (d, J = 1.5 Hz, 1 H);6-carboxamide 7.91 (m, 2 H); 8.05 (s, 1 H); 8.19 (m, 3 H); 9.19 (s, 1H); 12.96 (broad s, 1 H) I-77 II-5 IIIb-30 2-({4-[3-(2-Hydroxyethyl)-1.26 (d, J = 6.1 Hz, 6 H); 1.52 (dq, J = 7.0 A4-methylpiperazin-1-yl]-2- and 14.0 Hz, 1 H); 1.77 (m, 1 H); 577(propan-2- 2.26 (m, 5 H); 2.48 (masked m, 1 H); 0.64yloxy)phenyl}amino)-7-(2- 2.74 (m, 2 H); 3.38 (m, 2 H); 3.53 (t, J = 6.7Hz, methoxyphenyl)thieno[3,2- 2 H); 3.70 (s, 3 H); 4.44 (broad s, 1d]pyrimidine-6- H); 4.64 (spt, J = 6.0 Hz, 1 H); 6.30 (dd, carboxamide J= 2.3 and 8.9 Hz, 1 H); 6.60 (d, J = 2.4 Hz, 1 H); 6.86 (broad s, 1 H);7.12 (t, J = 7.5 Hz, 1 H); 7.18 (d, J = 8.3 Hz, 1 H); 7.47 (m, 2 H);7.71 (broad s, 1 H); 7.77 (s, 1 H); 7.94 (d, J = 9.0 Hz, 1 H); 9.15 (s,1 H) I-78 II-31 IIIb-7 7-(2-methoxypyridin-3-yl)- 1.28 (d, J = 5.9 Hz, 6H); 1.64 (m, 4 H); A 2-{[5-methyl-4-(1- 1.96 (t, J = 10.3 Hz, 2 H); 2.09(s, 3 H); 547 methylpiperidin-4-yl)-2- 2.19 (s, 3 H); 2.55 (m, 1 H);2.86 (d, 0.63 (propan-2- J = 10.8 Hz, 2 H); 3.79 (s, 3 H); 4.62 (spt,yloxy)phenyl]amino}thieno[3, J = 6.0 Hz, 1 H); 6.81 (s, 1 H); 7.16 (dd,2-d]pyrimidine-6- J = 5.4 and 11.7 Hz, 1 H); 7.46 (broad s, carboxamide1 H); 7.71 (broad s, 1 H); 7.86 (s, 1 H); 7.91 (d, J = 6.8 Hz, 1 H);8.00 (s, 1 H); 8.27 (d, J = 3.9 Hz, 1 H); 9.24 (s, 1 H) I-79 II-31IIIb-25 7-(2-Methoxypyridin-3-yl)- 1.26 (d, J = 5.9 Hz, 6 H); 2.22 (s, 3H); A 2-{[4-(4-methylpiperazin- 2.44 (m, 4 H); 3.05 (m, 4 H); 3.80 (s, 3534 1-yl)-2-(propan-2- H); 4.65 (spt, J = 6.0 Hz, 1 H); 6.34 (dd, 0.60yloxy)phenyl]amino}thieno[3, J = 2.3 and 8.9 Hz, 1 H); 6.62 (d, J = 2.4Hz, 2-d]pyrimidine-6- 1 H); 7.17 (dd, J = 4.9 and 7.3 Hz, 1 carboxamideH); 7.45 (broad s, 1 H); 7.67 (broad s, 1 H); 7.83 (s, 1 H); 7.90 (dd, J= 2.0 and 7.3 Hz, 1 H); 7.94 (d, J = 8.8 Hz, 1 H); 8.26 (dd, J = 2.0 and5.1 Hz, 1 H); 9.18 (s, 1 H) I-80 II-5 IIIb-16 2-({4-[1-(2- 1.29 (d, J =5.9 Hz, 6 H); 1.64 (m, 4 H); A Hydroxyethyl)piperidin-4- 2.07 (m, 2 H);2.41 (m, 3 H); 2.98 (d, 562 yl]-2-(propan-2- J = 10.8 Hz, 2 H); 3.52(broad s, 2 H); 0.67 yloxy)phenyl}amino)-7-(2- 3.70 (s, 3 H); 4.37(broad s, 1 H); methoxyphenyl)thieno[3,2- 4.67 (spt, J = 6.0 Hz, 1 H);6.60 (d, J = 7.8 Hz, d]pyrimidine-6- 1 H); 6.87 (s, 1 H); 6.92 (broad s,1 H); carboxamide 7.13 (t, J = 7.1 Hz, 1 H); 7.20 (d, J = 8.3 Hz, 1 H);7.49 (m, 2 H); 7.75 (broad s, 1 H); 7.87 (s, 1 H); 8.14 (d, J = 8.3 Hz,1 H); 9.21 (s, 1 H) I-81 II-5 IIIb-48 7-(2-Methoxyphenyl)-2- 1.35 (d, J= 5.9 Hz, 6 H); 3.72 (s, 3 H); A {[4-(3-methoxypyridin-4- 3.91 (s, 3 H);4.72 (spt, J = 6.0 Hz, 1 H); 542 yl)-2-(propan-2- 6.96 (broad s, 1 H);6.98 (dd, J = 1.7 and 0.78 yloxy)phenyl]amino}thieno[3, 8.6 Hz, 1 H);7.15 (t, J = 7.5 Hz, 1 H); 2-d]pyrimidine-6- 7.21 (d, J = 8.3 Hz, 1 H);7.26 (d, J = 1.7 Hz, carboxamide 1 H); 7.37 (d, J = 4.6 Hz, 1 H); 7.51(m, 2 H); 7.76 (broad s, 1 H); 8.04 (s, 1 H); 8.26 (d, J = 4.6 Hz, 1 H);8.37 (d, J = 8.3 Hz, 1 H); 8.43 (s, 1 H); 9.29 (s, 1 H) I-82 II-5IIIb-56 7-(2-Methoxyphenyl)-2- 1.27 (d, J = 6.1 Hz, 6 H); 2.22 (s, 3 H);A {[6-(4-methylpiperazin-1- 2.40 (t, J = 4.7 Hz, 4 H); 3.37 (m, 4 H);534 yl)-2-(propan-2- 3.70 (s, 3 H); 5.19 (spt, J = 6.1 Hz, 1 H); 0.68yloxy)pyridin-3- 6.16 (d, J = 8.5 Hz, 1 H); 6.85 (broad s, 1yl]amino}thieno[3,2- H); 7.11 (t, J = 7.4 Hz, 1 H); 7.17 (d,d]pyrimidine-6- J = 8.2 Hz, 1 H); 7.42 (d, J = 7.4 Hz, 1 H); carboxamide7.47 (t, J = 7.2 Hz, 1 H); 7.73 (broad s, 1 H); 7.83 (s, 1 H); 8.02 (d,J = 7.7 Hz, 1 H); 9.15 (s, 1 H) I-83 II-5 IIIb-10 7-(2-Methoxyphenyl)-2-1.11 (m, 12 H); 1.30 (d, J = 5.9 Hz, 6 H); A {[4-(1,2,2,6,6- 1.56 (m, J= 12.7 Hz, 4 H); 2.14 to 588 pentamethylpiperidin-4- 2.29 (m, 3 H); 2.88(broad s, 1 H); 3.71 (s, 3 0.78 yl)-2-(propan-2- H); 4.69 (spt, J = 5.9Hz, 1 H); 6.61 (d, yloxy)phenyl]amino}thieno[3, J = 8.8 Hz, 1 H); 6.91(m, 2 H); 7.14 (t, 2-d]pyrimidine-6- J = 7.3 Hz, 1 H); 7.20 (d, J = 8.3Hz, 1 H); carboxamide 7.49 (m, 2 H); 7.74 (broad s, 1 H); 7.88 (s, 1 H);8.15 (d, J = 8.3 Hz, 1 H); 9.22 (s, 1 H) I-84 II-5 IIIb-132-({4-[(2S,4S)-2-Ethyl-1- 0.84 (t, J = 7.3 Hz, 3 H); 1.30 (d, J = 5.9Hz, A methylpiperidin-4-yl]-2- 6 H); 1.33 to 1.70 (m, 6 H); 1.86 (m, 560(propan-2- 1 H); 2.12 (m, 1 H); 2.18 (s, 3 H); 0.74yloxy)phenyl}amino)-7-(2- 2.44 (m, 1 H); 2.89 (dt, J = 2.9 and 11.2 Hz,1 methoxyphenyl)thieno[3,2- H); 3.71 (s, 3 H); 4.68 (spt, J = 6.1 Hz, 1d]pyrimidine-6- H); 6.60 (dd, J = 1.6 and 8.4 Hz, 1 H); carboxamide 6.87(d, J = 1.5 Hz, 1 H); 6.90 (broad s, 1 H); 7.14 (t, J = 7.5 Hz, 1 H);7.20 (d, J = 7.8 Hz, 1 H); 7.49 (m, 2 H); 7.74 (broad s, 1 H); 7.87 (s,1 H); 8.13 (d, J = 8.3 Hz, 1 H); 9.22 (s, 1 H) I-85 II-5 IIIb-132-({4-[(2S,4R)-2-Ethyl-1- 0.86 (t, J = 7.5 Hz, 3 H); 1.30 (dd, J = 1.2 Amethylpiperidin-4-yl]-2- and 6.1 Hz, 6 H); 1.43 to 1.84 (m, 6 H); 560(propan-2- 2.30 (s, 3 H); 2.45 (m, 1 H); 2.55 to 0.76yloxy)phenyl}amino)-7-(2- 2.74 (m, 3 H); 3.71 (s, 3 H); 4.68 (spt, J =5.9 Hz, methoxyphenyl)thieno[3,2- 1 H); 6.62 (dd, J = 1.7 and 8.6 Hz, 1d]pyrimidine-6- H); 6.89 (d, J = 1.7 Hz, 1 H); 6.92 (broad carboxamides, 1 H); 7.14 (t, J = 7.5 Hz, 1 H); 7.20 (d, J = 8.1 Hz, 1 H); 7.49 (m,2 H); 7.74 (broad s, 1 H); 7.87 (s, 1 H); 8.13 (d, J = 8.1 Hz, 1 H);9.22 (s, 1 H) I-86 II-31 IIIb-5 7-(2-Methoxypyridin-3-yl)- 1.00 (d, J =6.4 Hz, 6 H); 1.30 (d, J = 5.9 Hz, A 2-({2-(propan-2-yloxy)-4- 6 H);1.58 (m, 2 H); 1.72 (m, 2 H); 561 [1-(propan-2-yl)piperidin- 2.20 (t, J= 10.6 Hz, 2 H); 2.40 (m, 0.69 4- J = 12.0 Hz, 1 H); 2.72 (m, 1 H); 2.88(d, yl]phenyl}amino)thieno[3, J = 9.3 Hz, 2 H); 3.80 (s, 3 H); 4.68 (m,1 2-d]pyrimidine-6- H); 6.64 (d, J = 8.1 Hz, 1 H); 6.88 (s, 1carboxamide H); 7.19 (t, J = 5.9 Hz, 1 H); 7.48 (broad s, 1 H); 7.70(broad s, 1 H); 7.92 (m, 2 H); 8.11 (d, J = 8.1 Hz, 1 H); 8.28 (d, J =3.7 Hz, 1 H); 9.24 (s, 1 H) I-87 II-36 IIIb-3 7-(5-Fluoro-2- 1.29 (d, J= 5.9 Hz, 6 H); 1.56 to 1.75 (m, A methoxypyridin-3-yl)-2- 4 H); 1.98(t, J = 11.0 Hz, 2 H); 2.21 (s, 3 551 {[4-(1-methylpiperidin-4- H); 2.40(m, 1 H); 2.87 (d, J = 11.2 Hz, 2 0.67 yl)-2-(propan-2- H); 3.78 (s, 3H); 4.67 (spt, J = 6.1 Hz, 1 yloxy)phenyl]amino}thieno[3, H); 6.64 (dd,J = 1.5 and 8.3 Hz, 1 H); 2-d]pyrimidine-6- 6.89 (d, J = 1.7 Hz, 1 H);7.66 (m, 2 H); carboxamide 7.93 (dd, J = 2.9 and 8.8 Hz, 1 H); 7.99 (s,1 H); 8.09 (d, J = 8.3 Hz, 1 H); 8.26 (d, J = 3.2 Hz, 1 H); 9.25 (s, 1H) I-88 II-36 IIIb-5 7-(5-Fluoro-2- 1.01 (d, J = 6.1 Hz, 6 H); 1.29 (d,J = 6.1 Hz, A methoxypyridin-3-yl)-2- 6 H); 1.48 to 1.66 (m, 2 H); 1.75(s, 579 ({2-(propan-2-yloxy)-4-[1- 2 H); 2.14 to 2.29 (m, 2 H); 2.41(broad 0.72 (propan-2-yl)piperidin-4- s, 1 H); 2.73 (broad s, 1 H); 2.84to yl]phenyl}amino)thieno[3, 2.95 (m, 2 H); 3.78 (s, 3 H); 4.67 (spt, J= 6.2 Hz, 2-d]pyrimidine-6- 1 H); 6.63 (dd, J = 1.6 and 8.4 Hz, 1carboxamide H); 6.89 (d, J = 1.2 Hz, 1 H); 7.61 to 7.74 (m, 2 H); 7.93(dd, J = 3.1 and 8.9 Hz, 1 H); 7.99 (s, 1 H); 8.09 (d, J = 8.3 Hz, 1 H);8.26 (d, J = 2.9 Hz, 1 H); 9.25 (s, 1 H) I-89 II-36 IIIb-77-(5-Fluoro-2- 1.28 (d, J = 6.1 Hz, 6 H); 1.63 (m, 4 H); Amethoxypyridin-3-yl)-2- 1.99 (t, J = 10.5 Hz, 2 H); 2.09 (s, 3 H); 565{[5-methyl-4-(1- 2.20 (s, 3 H); 2.57 (m, 1 H); 2.87 (d, 0.68methylpiperidin-4-yl)-2- J = 11.0 Hz, 2 H); 3.78 (s, 3 H); 4.62 (spt,(propan-2- J = 6.1 Hz, 1 H); 6.81 (s, 1 H); yloxy)phenyl]amino}thieno[3,7.61 (broad s, 1 H); 7.71 (broad s, 1 H); 2-d]pyrimidine-6- 7.91 (m, 2H); 7.98 (s, 1 H); 8.25 (d, J = 2.9 Hz, carboxamide 1 H); 9.25 (s, 1 H)I-90 II-37 IIIb-3 7-(6-Methoxypyridin-2-yl)- 1.31 (d, J = 5.9 Hz, 6 H);1.76 to 2.03 (m, A 2-{[4-(1-methylpiperidin-4- 4 H); 2.55 to 2.63(masked m, 2 H); 533 yl)-2-(propan-2- 2.68 to 2.79 (m, 4 H); 3.89 (s, 3H); 0.70 yloxy)phenyl]amino}thieno[3, 4.67 (m, 1 H); 6.79 (d, J = 8.3Hz, 1 H); 2-d]pyrimidine-6- 6.88 (dd, J = 3.5 and 5.3 Hz, 1 H); 6.93(broad carboxamide s, 1 H); 7.86 to 7.93 (m, 4 H); 8.09 (s, 1 H); 8.25(s, 3 H); 9.26 (s, 1 H) I-91 II-2 IIIb-16 7-(2-Chlorophenyl)-2-({4- 1.28(d, J = 5.9 Hz, 6 H); 1.53 to 1.72 (m, A [1-(2- 4 H); 1.96 to 2.07 (m, 2H); 2.34 (m, 1 566 hydroxyethyl)piperidin-4- H); 2.40 (t, J = 6.4 Hz, 2H); 2.95 (d, 0.69 yl]-2-(propan-2- J = 11.5 Hz, 2 H); 3.51 (q, J = 5.9Hz, 2 yloxy)phenyl}amino)thieno[3, H); 4.31 (t, J = 5.4 Hz, 1 H); 4.66(spt, 2-d]pyrimidine-6- J = 6.0 Hz, 1 H); 6.54 (d, J = 8.3 Hz, 1 H);carboxamide 6.86 (s, 1 H); 7.18 (broad s, 1 H); 7.46 to 7.57 (m, 3 H);7.63 (m, 1 H); 7.79 (broad s, 1 H); 7.91 (s, 1 H); 8.01 (d, J = 8.3 Hz,1 H); 9.25 (s, 1 H) I-92 II-5 IIIb-57 7-(2-Methoxyphenyl)-2- 1.34 (d, J= 6.1 Hz, 6 H); 1.98 (m, 4 H); A {[6-(1-methylpiperidin-4- 2.76 (s, 4H); 3.02 (s, 2 H); 3.45 (m, 533 yl)-2-(propan-2- J = 5.4 Hz, 2 H); 3.70(s, 3 H); 5.30 (spt, 0.71 yloxy)pyridin-3- J = 6.2 Hz, 1 H); 6.66 (d, J= 7.6 Hz, 1 H); yl]amino}thieno[3,2- 6.92 (broad s, 1 H); 7.12 (td, J =0.9 and d]pyrimidine-6- 7.4 Hz, 1 H); 7.19 (d, J = 8.1 Hz, 1 H);carboxamide 7.45 (dd, J = 1.6 and 7.5 Hz, 1 H); 7.49 (td, J = 1.7 and8.3 Hz, 1 H); 7.76 (broad s, 1 H); 7.98 (s, 1 H); 8.36 (d, J = 8.1 Hz, 1H); 9.27 (s, 1 H); 9.74 (broad s, 1 H) I-93 II-5 IIIb-45 2-{[4-(1,7-1.27 (d, J = 6.1 Hz, 6 H); 1.54 (m, 1 H); A Diazaspiro[4.4]non-7-yl)-1.89 (m, 4 H); 2.15 (m, 2 H); 2.35 (m, 1 559 2-(propan-2- H); 3.15 (t, J= 7.1 Hz, 1 H); 0.71 yloxy)phenyl]amino}-7-(2- 3.23 (masked m, 2 H);3.41 (s, 1 H); 3.70 (s, methoxyphenyl)thieno[3,2- 3 H); 4.63 (spt, J =6.0 Hz, 1 H); d]pyrimidine-6- 5.96 (dd, J = 2.6 and 8.9 Hz, 1 H); 6.22(d, carboxamide J = 2.2 Hz, 1 H); 6.83 (broad s, 1 H); 7.11 (td, J = 1.1and 7.5 Hz, 1 H); 7.17 (d, J = 8.1 Hz, 1 H); 7.47 (m, 2 H); 7.71 (broads, 1 H); 7.73 (s, 1 H); 7.88 (d, J = 8.8 Hz, 1 H); 9.12 (s, 1 H) I-94II-31 IIIb-36 2-({4-[3- 0.98 (t, J = 7.1 Hz, 6 H); 1.25 (d, J = 5.9 Hz,A (Diethylamino)pyrrolidin- 6 H); 1.80 (m, 1 H); 2.12 (m, 1 H); 5761-yl]-2-(propan-2- 2.59 (m, 4 H); 2.98 (t, J = 7.8 Hz, 1 H); 0.67yloxy)phenyl}amino)-7-(2- 3.18 (m, 1 H); 3.38 to 3.42 (partiallymethoxypyridin-3- masked m, 3 H); 3.79 (s, 3 H);yl)thieno[3,2-d]pyrimidine- 4.63 (spt, J = 5.9 Hz, 1 H); 5.97 (dd, J =2.4 6-carboxamide and 8.8 Hz, 1 H); 6.21 (d, J = 2.4 Hz, 1 H); 7.15 (dd,J = 5.1 and 7.3 Hz, 1 H); 7.43 (broad s, 1 H); 7.66 (broad s, 1 H); 7.77(s, 1 H); 7.80 (d, J = 8.8 Hz, 1 H); 7.89 (dd, J = 1.7 and 7.3 Hz, 1 H);8.25 (dd, J = 1.7 and 5.1 Hz, 1 H); 9.13 (s, 1 H) I-95 II-38 IIIb-342-({4-[3- 1.24 (d, J = 6.1 Hz, 6 H); 1.79 (m, 1 H); A(Dimethylamino)pyrrolidin- 2.13 (m, 1 H); 2.21 (s, 6 H); 2.78 (m, 1 5201-yl]-2-(propan-2- H); 3.01 (t, J = 7.8 Hz, 1 H); 3.21 (m, 1 0.67yloxy)phenyl}amino)-7-(1- H); 3.28 to 3.44 (partially masked m, 2methyl-1H-pyrrol-2- H); 3.48 (s, 3 H); 4.61 (spt, J = 6.1 Hz, 1yl)thieno[3,2-d]pyrimidine- H); 6.02 (dd, J = 2.4 and 8.8 Hz, 1 H);6-carboxamide 6.17 to 6.28 (m, 3 H); 6.80 (broad s, 1 H); 7.04 (t, J =2.2 Hz, 1 H); 7.74 (d, J = 8.8 Hz, 1 H); 7.86 (s, 1 H); 7.91 (broad s, 1H); 9.12 (s, 1 H) I-96 II-38 IIIb-3 2-{[4-(1-Methylpiperidin-4- 1.29 (d,J = 5.9 Hz, 6 H); 1.63 to 1.88 (m, A yl)-2-(propan-2- 4 H); 2.24 to 2.58(partially masked m, 6 505 yloxy)phenyl]amino}-7-(1- H); 3.08 (m, 2 H);3.48 (s, 3 H); 4.66 (m, 0.68 methyl-1H-pyrrol-2- 1 H); 6.22 (t, J = 3.2Hz, 1 H); 6.30 (dd, yl)thieno[3,2-d]pyrimidine- J = 1.3 and 3.8 Hz, 1H); 6.69 (broad d, 6-carboxamide J = 8.1 Hz, 1 H); 6.85 (broad s, 1 H);6.89 (broad s, 1 H); 7.08 (broad s, 1 H); 7.96 (broad s, 1 H); 8.00 (s,1 H); 8.10 (d, J = 8.1 Hz, 1 H); 9.23 (s, 1 H) I-97 II-39 IIIb-32-{[4-(1-Methylpiperidin-4- 1.27 (d, J = 6.1 Hz, 6 H); 1.54 to 1.74 (m,A yl)-2-(propan-2- 4 H); 1.97 (m, 2 H); 2.20 (s, 3 H); 517yloxy)phenyl]amino}-7-(2- 2.29 (s, 3 H); 2.38 (m, 1 H); 2.86 (m, 2 H);0.49 methylpyridin-3- 4.65 (m, 1 H); 6.55 (dd, J = 2.1 and 8.3 Hz,yl)thieno[3,2-d]pyrimidine- 1 H); 6.87 (d, J = 2.1 Hz, 1 H);6-carboxamide 7.36 (dd, J = 4.9 and 7.6 Hz, 1 H); 7.39 (broad s, 1 H);7.70 (dd, J = 2.0 and 7.6 Hz, 1 H); 7.79 (broad s, 1 H); 7.92 (d, J =8.3 Hz, 1 H); 7.95 (s, 1 H); 8.56 (dd, J = 2.0 and 4.9 Hz, 1 H); 9.26(s, 1 H) I-98 II-40 IIIb-3 7-(Furan-2-yl)-2-{[4-(1- 1.29 (d, J = 6.1 Hz,6 H); 1.62 to 1.80 (m, A methylpiperidin-4-yl)-2- 4 H); 1.97 (m, 2 H);2.20 (s, 3 H); 492 (propan-2- 2.45 (m, 1 H); 2.88 (m, 2 H); 4.68 (m, 1H); 0.65 yloxy)phenyl]amino}thieno[3, 6.68 (dd, J = 1.8 and 3.3 Hz, 1H); 2-d]pyrimidine-6- 6.86 (dd, J = 2.1 and 8.4 Hz, 1 H); 6.95 (d,carboxamide J = 2.1 Hz, 1 H); 7.33 (broad d, J = 3.3 Hz, 1 H); 7.84(broad d, J = 1.8 Hz, 1 H); 7.90 (broad s, 1 H); 8.09 (broad s, 1 H);8.12 (s, 1 H); 8.20 (d, J = 8.1 Hz, 1 H); 9.20 (s, 1 H) I-99 II-41IIIb-3 7-[5-(Aminomethyl)furan- 1,.0 (d, J = 6.1 Hz, 6 H); 1.59 to 1.80(m, A 2-yl]-2-{[4-(1- 4 H); 1.98 (m, 2 H); 2.21 (s, 3 H); 521methylpiperidin-4-yl)-2- 2.43 (partially masked m, 1 H); 2.88 (m, 2 H);0.48 (propan-2- 3.77 (s, 2 H); 4.69 (m, 1 H); 6.42 (broadyloxy)phenyl]amino}thieno[3, d, J = 2.9 Hz, 1 H); 6.84 (broad d, J = 8.3Hz, 2-d]pyrimidine-6- 1 H); 6.95 (broad s, 1 H); carboxamide 7.20 (broadd, J = 2.9 Hz, 1 H); 7.94 (broad s, 1 H); 8.04 (broad s, 1 H); 8.10 (s,1 H); 8.22 (d, J = 8.3 Hz, 1 H); 9.19 (s, 1 H) I-100 II-31 IIIb-267-(2-Methoxypyridin-3-yl)- 1.28 (d, J = 6.1 Hz, 6 H); 2.05 (s, 3 H); A2-{[5-methyl-4-(4- 2.23 (s, 3 H); 2.46 (m, 4 H); 2.78 (m, 4 548methylpiperazin-1-yl)-2- H); 3.79 (s, 3 H); 4.60 (spt, J = 6.1 Hz, 10.63 (propan-2- H); 6.69 (s, 1 H); 7.16 (dd, J = 5.1 andyloxy)phenyl]amino}thieno[3, 7.3 Hz, 1 H); 7.43 (broad s, 1 H);2-d]pyrimidine-6- 7.69 (broad s, 1 H); 7.82 (s, 1 H); 7.91 (dd,carboxamide J = 2.0 and 7.3 Hz, 1 H); 8.01 (s, 1 H); 8.27 (dd, J = 2.0and 5.1 Hz, 1 H); 9.22 (s, 1 H) I-101 II-43 IIIb-32-{[4-(1-Methylpiperidin-4- 1.32 (d, J = 6.1 Hz, 6 H); 1.61 to 1.79 (m,A yl)-2-(propan-2- 4 H); 1.97 (m, 2 H); 2.20 (s, 3 H); 491yloxy)phenyl]amino}-7- 2.42 (m, 1 H); 2.88 (m, 2 H); 4.70 (m, 1 H); 0.64(1H-pyrrol-3-yl)thieno[3,2- 6.56 (m, 1 H); 6.81 (dd, J = 2.0 and 8.5 Hz,d]pyrimidine-6- 1 H); 6.92 (m, 2 H); 7.51 (m, 1 H); carboxamide 7.60(broad s, 1 H); 7.88 (broad s, 1 H); 7.92 (s, 1 H); 8.37 (d, J = 8.5 Hz,1 H); 9.16 (s, 1 H); 11.18 (broad s, 1 H) I-102 II-31 IIIb-34 2-({4-[3-1.25 (d, J = 6.1 Hz, 6 H); 1.79 (m, 1 H); A (Dimethylamino)pyrrolidin-2.13 (m, 1 H); 2.21 (s, 6 H); 2.78 (m, 1 548 1-yl]-2-(propan-2- H); 3.00(m, 1 H); 3.21 (m, 1 H); 3.25 to 0.62 yloxy)phenyl}amino)-7-(2- 3.42(partially masked m, 2 H); 3.79 (s, methoxypyridin-3- 3 H); 4.63 (m, 1H); 5.98 (dd, J = 2.5 and yl)thieno[3,2-d]pyrimidine- 9.0 Hz, 1 H); 6.21(d, J = 2.5 Hz, 1 H); 6-carboxamide 7.15 (dd, J = 5.1 and 7.3 Hz, 1 H);7.42 (broad s, 1 H); 7.66 (broad s, 1 H); 7.77 (s, 1 H); 7.80 (broad d,J = 9.0 Hz, 1 H); 7.89 (dd, J = 2.1 and 7.3 Hz, 1 H); 8.25 (dd, J = 2.1and 5.1 Hz, 1 H); 9.13 (s, 1 H) I-103 II-44 IIIb-57-(2-Ethoxypyridin-3-yl)- 0.99 (d, J = 6.6 Hz, 6 H); 1.19 (t, J = 7.1Hz, A 2-({2-(propan-2-yloxy)-4- 3 H); 1.29 (d, J = 6.1 Hz, 6 H); 575[1-(propan-2-yl)piperidin- 1.59 (m, 2 H); 1.72 (m, 2 H); 2.18 (m, 2 H);0.72 4- 2.39 (m, 1 H); 2.70 (m, 1 H); 2.87 (m, 2yl]phenyl}amino)thieno[3, H); 4.28 (q, J = 7.1 Hz, 2 H); 4.68 (m, 12-d]pyrimidine-6- H); 6.64 (dd, J = 2.3 and 8.5 Hz, 1 H); carboxamide6.88 (d, J = 2.3 Hz, 1 H); 7.17 (dd, J = 5.1 and 7.3 Hz, 1 H); 7.48(broad s, 1 H); 7.69 (broad s, 1 H); 7.91 (s, 1 H); 7.93 (dd, J = 2.1and 7.3 Hz, 1 H); 8.13 (d, J = 8.5 Hz, 1 H); 8.25 (dd, J = 2.1 and 5.1Hz, 1 H); 9.23 (s, 1 H) I-104 II-44 IIIb-7 7-(2-Ethoxypyridin-3-yl)-1.17 (t, J = 7.1 Hz, 3 H); 1.28 (d, J = 6.1 Hz, A 2-{[5-methyl-4-(1- 6H); 1.50 to 1.71 (m, 4 H); 1.97 (m, 561 methylpiperidin-4-yl)-2- 2 H);2.09 (s, 3 H); 2.19 (s, 3 H); 0.67 (propan-2- 2.54 (partially masked m,1 H); 2.86 (m, 2 H); yloxy)phenyl]amino}thieno[3, 4.28 (q, J = 7.1 Hz, 2H); 4.62 (m, 1 H); 2-d]pyrimidine-6- 6.81 (s, 1 H); 7.14 (dd, J = 5.1and 7.3 Hz, carboxamide 1 H); 7.46 (broad s, 1 H); 7.69 (broad s, 1 H);7.85 (s, 1 H); 7.93 (dd, J = 2.1 and 7.3 Hz, 1 H); 8.02 (s, 1 H); 8.24(dd, J = 2.1 and 5.1 Hz, 1 H); 9.24 (s, 1 H) I-105 II-5 IIIb-267-(2-Methoxyphenyl)-2- 1.28 (d, J = 5.9 Hz, 6 H); 2.00 (s, 3 H); A{[5-methyl-4-(4- 2.22 (s, 3 H); 2.43 (m, 4 H); 2.77 (t, 547methylpiperazin-1-yl)-2- J = 4.4 Hz, 4 H); 3.69 (s, 3 H); 4.59 (spt,0.68 (propan-2- J = 6.1 Hz, 1 H); 6.68 (s, 1 H);yloxy)phenyl]amino}thieno[3, 6.82 (broad s, 1 H); 7.13 (t, J = 7.3 Hz, 1H); 2-d]pyrimidine-6- 7.19 (d, J = 8.3 Hz, 1 H); 7.48 (m, 2 H);carboxamide 7.73 (broad s, 1 H); 7.77 (s, 1 H); 8.03 (s, 1 H); 9.19 (s,1 H) I-106 II-44 IIIb-3 7-(2-Ethoxypyridin-3-yl)- 1.19 (t, J = 7.1 Hz, 3H); 1.29 (d, J = 6.1 Hz, A 2-{[4-(1-methylpiperidin-4- 6 H); 1.58 to1.75 (m, 4 H); 1.93 (m, 547 yl)-2-(propan-2- 2 H); 2.19 (s, 3 H); 2.39(m, 1 H); 0.67 yloxy)phenyl]amino}thieno[3, 2.85 (d, J = 11.0 Hz, 2 H);4.28 (q, J = 7.1 Hz, 2 2-d]pyrimidine-6- H); 4.67 (quin, J = 6.1 Hz, 1H); 6.64 (dd, carboxamide J = 1.7 and 8.3 Hz, 1 H); 6.88 (d, J = 1.5 Hz,1 H); 7.16 (dd, J = 5.1 and 7.3 Hz, 1 H); 7.48 (broad s, 1 H); 7.69(broad s, 1 H); 7.93 (m, 2 H); 8.13 (d, J = 8.3 Hz, 1 H); 8.24 (dd, J =2.0 and 5.1 Hz, 1 H); 9.23 (s, 1 H) I-107 II-44 IIIb-257-(2-Ethoxypyridin-3-yl)- 1.20 (t, J = 7.1 Hz, 3 H); 1.26 (d, J = 5.9Hz, A 2-{[4-(4-methylpiperazin- 6 H); 2.22 (s, 3 H); 2.44 (m, 4 H); 5481-yl)-2-(propan-2- 3.05 (m, 4 H); 4.28 (q, J = 7.1 Hz, 2 H); 0.85yloxy)phenyl]amino}thieno[3, 4.65 (m, 1 H); 6.34 (dd, J = 2.5 and 8.8Hz, 2-d]pyrimidine-6- 1 H); 6.62 (d, J = 2.5 Hz, 1 H); carboxamide 7.15(dd, J = 5.1 and 7.3 Hz, 1 H); 7.46 (broad s, 1 H); 7.67 (broad s, 1 H);7.82 (s, 1 H); 7.91 (dd, J = 2.2 and 7.3 Hz, 1 H); 7.96 (d, J = 8.8 Hz,1 H); 8.23 (dd, J = 2.2 and 5.1 Hz, 1 H); 9.18 (s, 1 H) I-108 II-45IIIb-25 7-(2-Methoxy-5- 1.26 (d, J = 5.9 Hz, 6 H); 2.22 (s, 3 H); Amethylpyridin-3-yl)-2-{[4- 2.32 (s, 3 H); 2.45 (m, 4 H); 3.06 (m, 4 548(4-methylpiperazin-1-yl)- H); 3.76 (s, 3 H); 4.65 (spt, J = 6.0 Hz, 10.63 2-(propan-2- H); 6.33 (dd, J = 2.4 and 8.8 Hz, 1 H);yloxy)phenyl]amino}thieno[3, 6.64 (d, J = 2.4 Hz, 1 H); 7.42 (broad s, 12-d]pyrimidine-6- H); 7.65 (broad s, 1 H); 7.77 (d, J = 2.2 Hz,carboxamide 1 H); 7.85 (s, 1 H); 7.94 (d, J = 8.8 Hz, 1 H); 8.07 (d, J =2.4 Hz, 1 H); 9.17 (s, 1 H) I-109 II-45 IIIb-3 7-(2-Methoxy-5- 1.30 (d,J = 6.1 Hz, 6 H); 1.54 to 1.77 (m, A methylpyridin-3-yl)-2-{[4- 4 H);1.94 (td, J = 2.3 and 11.6 Hz, 2 H); 547 (1-methylpiperidin-4-yl)-2-2.19 (s, 3 H); 2.34 (s, 3 H); 2.40 (m, 1 0.67 (propan-2- H); 2.85 (d, J= 11.2 Hz, 2 H); 3.77 (s, 3 yloxy)phenyl]amino}thieno[3, H); 4.68 (spt,J = 6.1 Hz, 1 H); 6.64 (dd, 2-d]pyrimidine-6- J = 1.5 and 8.3 Hz, 1 H);6.90 (d, J = 1.7 Hz, carboxamide 1 H); 7.45 (broad s, 1 H); 7.67 (broads, 1 H); 7.80 (d, J = 2.2 Hz, 1 H); 7.94 (s, 1 H); 8.09 (dd, J = 0.7 and2.4 Hz, 1 H); 8.14 (d, J = 8.3 Hz, 1 H); 9.23 (s, 1 H) I-110 II-36IIIb-25 7-(5-Fluoro-2- 1.25 (d, J = 6.1 Hz, 6 H); 2.22 (s, 3 H); Amethoxypyridin-3-yl)-2- 2.43 (m, 4 H); 3.06 (m, 4 H); 3.78 (s, 3 552{[4-(4-methylpiperazin-1- H); 4.64 (spt, J = 6.0 Hz, 1 H); 6.33 (dd,0.63 yl)-2-(propan-2- J = 2.4 and 8.8 Hz, 1 H); 6.63 (d, J = 2.4 Hz,yloxy)phenyl]amino}thieno[3, 1 H); 7.62 (broad s, 1 H);2-d]pyrimidine-6- 7.68 (broad s, 1 H); 7.87 to 7.93 (m, 3 H);carboxamide 8.24 (d, J = 2.9 Hz, 1 H); 9.19 (s, 1 H) I-111 II-45 IIIb-77-(2-Methoxy-5- 1.28 (d, J = 6.1 Hz, 6 H); 1.65 (m, 4 H); Amethylpyridin-3-yl)-2-{[5- 2.05 (s, 3 H); 2.25 (m, 8 H); 2.55 (d, 561methyl-4-(1- J = 8.3 Hz, 1 H); 2.90 (d, J = 8.6 Hz, 2 H); 0.67methylpiperidin-4-yl)-2- 3.76 (s, 3 H); 4.61 (spt, J = 6.1 Hz, 1 H);(propan-2- 6.80 (s, 1 H); 7.35 (broad s, 1 H);yloxy)phenyl]amino}thieno[3, 7.68 (d, J = 2.4 Hz, 1 H); 7.71 (broad s, 1H); 2-d]pyrimidine-6- 7.88 (s, 1 H); 7.96 (s, 1 H); 8.09 (d, carboxamideJ = 1.5 Hz, 1 H); 9.23 (s, 1 H) I-112 II-46 IIIb-32-{[4-(1-Methylpiperidin-4- 1.30 (d, J = 6.1 Hz, 6 H); 1.68 (m, 4 H); Ayl)-2-(propan-2- 1.97 (m, 2 H); 2.20 (s, 3 H); 2.41 (m, 1 506yloxy)phenyl]amino}-7-(1- H); 2.87 (d, J = 11.2 Hz, 2 H); 3.99 (s, 30.66 methyl-1H-pyrazol-3- H); 4.68 (spt, J = 6.1 Hz, 1 H); 6.79 (dd,yl)thieno[3,2-d]pyrimidine- J = 1.6 and 8.4 Hz, 1 H); 6.93 (d, J = 1.7Hz, 6-carboxamide 1 H); 7.17 (d, J = 2.2 Hz, 1 H); 7.98 (d, J = 2.2 Hz,1 H); 8.02 (s, 1 H); 8.04 (broad s, 1 H); 8.26 (d, J = 8.3 Hz, 1 H);9.23 (s, 1 H); 9.85 (broad s, 1 H) I-113 II-5 IIIb-312-({4-[3-(2-Methoxyethyl)- 1.26 (d, J = 5.8 Hz, 6 H); 1.62 (m, 1 H); A4-methylpiperazin-1-yl]-2- 1.86 (m, 1 H); 2.13 to 2.31 (m, 5 H); 591(propan-2- 2.71 (t, J = 9.6 Hz, 1 H); 2.79 (d, J = 11.5 Hz, 0.71yloxy)phenyl}amino)-7-(2- 1 H); 3.26 (s, 3 H); 3.35 to 3.49 (m,methoxyphenyl)thieno[3,2- 5 H); 3.70 (s, 3 H); 4.59 to 4.72 (m, 1d]pyrimidine-6- H); 6.30 (d, J = 8.5 Hz, H); 1 H). 6.60 (s, 1carboxamide H); 6.91 (broad s, 1 H); 7.12 (t, J = 7.4 Hz, 1 H); 7.18 (d,J = 8.2 Hz, 1 H); 7.48 (m, 2 H); 7.74 (broad s, 1 H); 7.79 (s, 1 H);7.95 (d, J = 9.6 Hz, 1 H); 9.16 (s, 1 H) I-114 II-5 IIIb-477-(2-Methoxyphenyl)-2- 1.26 (d, J = 6.1 Hz, 7 H); 1.51 (m, 1 H); A{[4-{(3R)-3- 1.71 (d, J = 8.8 Hz, 2 H); 2.21 (s, 3 H); 603[methyl(oxetan-3- 2.46 (broad s, 3 H); 3.48 (m, 2 H); 0.70yl)amino]piperidin-1-yl}-2- 3.70 (s, 3 H); 4.00 (quin, J = 6.8 Hz, 1 H);(propan-2- 4.50 (m, 4 H); 4.65 (spt, J = 5.9 Hz, 1 H);yloxy)phenyl]amino}thieno[3, 6.28 (d, J = 7.1 Hz, 1 H); 6.58 (d, J = 2.0Hz, 1 2-d]pyrimidine-6- H); 6.86 (broad s, 1 H); 7.12 (t, J = 7.6 Hz,carboxamide 1 H); 7.18 (d, J = 8.3 Hz, 1 H); 7.38 to 7.53 (m, 2 H); 7.71(broad s, 1 H); 7.76 (s, 1 H); 7.94 (d, J = 8.8 Hz, 1 H); 9.15 (s, 1 H)I-115 II-42 IIIb-3 7-(2-Methylfuran-3-yl)-2- 1.30 (d, J = 6.1 Hz, 6 H);1.57 to 1.77 (m, A {[4-(1-methylpiperidin-4- 4 H); 1.95 (m, 2 H); 2.19(s, 3 H); 506 yl)-2-(propan-2- 2.21 (s, 3 H); 2.40 (m, 1 H); 2.86 (m, 2H); 0.68 yloxy)phenyl]amino}thieno[3, 4.68 (m, 1 H); 6.68 (d, J = 2.0Hz, 1 H); 2-d]pyrimidine-6- 6.73 (dd, J = 2.3 and 8.3 Hz, 1 H);carboxamide 6.90 (d, J = 2.3 Hz, 1 H); 7.30 (broad s, 1 H); 7.71 (d, J =2.0 Hz, 1 H); 7.90 (broad s, 1 H); 7.95 (s, 1 H); 8.24 (d, J = 8.3 Hz, 1H); 9.22 (s, 1 H) I-116 II-37 IIIb-7 7-(6-Methoxypyridin-2-yl)- 1.29 (d,J = 6.1 Hz, 6 H); 1.62 (m, 4 H); A 2-{[5-methyl-4-(1- 1.95 to 2.06 (m, 2H); 2.20 (s, 3 H); 547 methylpiperidin-4-yl)-2- 2.21 (s, 3 H); 2.60 (m,1 H); 2.88 (d, J = 11.0 Hz, 0.70 (propan-2- 2 H); 3.88 (s, 3 H); 4.64(dt, J = 6.1 yloxy)phenyl]amino}thieno[3, and 11.9 Hz, 1 H); 6.85 (s, 1H); 2-d]pyrimidine-6- 6.89 (d, J = 7.8 Hz, 1 H); 7.88 (m, 3 H);carboxamide 7.97 (s, 1 H); 8.14 (s, 1 H); 8.20 (broad s, 1 H); 9.25 (s,1 H) I-117 II-31 IIIb-35 2-({4-[3- 1.28 (dd, J = 1.0 and 5.9 Hz, 6 H); A(Dimethylamino)pyrrolidin- 1.58 (m, 1 H); 1.86 (m, 1 H); 2.06 (s, 3 H);562 1-yl]-5-methyl-2-(propan- 2.18 (s, 3 H); 2.23 (dd, J = 6.0 and 9.2Hz, 0.70 2-yloxy)phenyl}amino)-7- 1 H); 2.41 (m, 5 H); 2.59 (m, 1 H);(2-methoxypyridin-3- 3.61 (m, 1 H); 3.79 (m, 3 H); 4.60 (dt,yl)thieno[3,2-d]pyrimidine- J = 6.3 and 12.2 Hz, 1 H); 6.77 (s, 1 H);6-carboxamide 7.16 (dd, J = 5.0 and 7.2 Hz, 1 H); 7.44 (broad s, 1 H);7.70 (broad s, 1 H); 7.84 (s, 1 H); 7.91 (dd, J = 2.0 and 7.3 Hz, 1 H);8.01 (s, 1 H); 8.27 (dd, J = 1.8 and 5.0 Hz, 1 H); 9.22 (s, 1 H) I-118II-5 IIIb-35 2-({4-[3- 1.28 (dd, J = 1.0 and 5.9 Hz, 6 H); A(Dimethylamino)pyrrolidin- 1.57 (m, 1 H); 1.85 (m, 1 H); 2.02 (s, 3 H);561 1-yl]-5-methyl-2-(propan- 2.18 (s, 3 H); 2.21 (dd, J = 6.0 and 9.2Hz, 0.75 2-yloxy)phenyl}amino)-7- 1 H); 2.38 (m, 1 H); 2.46 (s, 4 H);(2- 2.58 (dd, J = 7.2 and 8.9 Hz, 1 H); methoxyphenyl)thieno[3,2- 3.60(m, 1 H); 3.70 (s, 3 H); 4.60 (spt, J = 6.1 Hz, d]pyrimidine-6- 1 H);6.76 (s, 1 H); 6.82 (broad s, 1 carboxamide H); 7.13 (t, J = 7.5 Hz, 1H); 7.20 (d, J = 8.1 Hz, 1 H); 7.49 (m, 2 H); 7.73 (broad s, 1 H); 7.79(s, 1 H); 8.03 (s, 1 H); 9.20 (s, 1 H) I-119 II-19 IIIb-582-({3-[1-(Oxetan-3- 1.22 (d, J = 6.4 Hz, 6 H); 1.50 (qd, J = 3.4 Ayl)piperidin-4-yl]-1- and 12.2 Hz, 2 H); 1.74 (d, J = 11.5 Hz, 2 602(propan-2-yl)-1H-pyrazol- H); 1.83 (m, 2 H); 2.42 (tt, J = 3.8 and 0.595-yl}amino)-7-[2- 11.6 Hz, 1 H); 2.73 (d, J = 11.2 Hz, 2 H);(trifluoromethoxy)phenyl]thieno[3, 3.39 (s, 1 H); 4.43 to 4.51 (m, 3 H);2-d]pyrimidine-6- 4.57 (m, 2 H); 6.01 (s, 1 H); 7.36 (broad s, 1carboxamide H); 7.47 (m, 2 H); 7.60 (m, 2 H); 7.74 (broad s, 1 H); 9.26(s, 1 H); 9.40 (broad s, 1 H) I-120 II-47 IIIb-7 7-(2-Methoxy-6- 1.29(d, J = 6.1 Hz, 6 H); 1.56 to 1.73 (m, A methylpyridin-3-yl)-2-{[5- 4H); 2.03 (m, 2 H); 2.10 (s, 3 H); 561 methyl-4-(1- 2.23 (s, 3 H); 2.49(s, 3 H); 2.58 (m, 1 H); 0.68 methylpiperidin-4-yl)-2- 2.90 (d, J = 10.5Hz, 2 H); 3.77 (s, 3 H); (propan-2- 4.62 (spt, J = 6.0 Hz, 1 H); 6.80(s, 1 H); yloxy)phenyl]amino}thieno[3, 7.01 (d, J = 7.3 Hz, 1 H); 7.31(broad s, 1 2-d]pyrimidine-6- H); 7.71 (broad s, 1 H); 7.77 (d, J = 7.6Hz, carboxamide 1 H); 7.84 (s, 1 H); 8.03 (s, 1 H); 9.22 (s, 1 H) I-121II-47 IIIb-25 7-(2-Methoxy-6- 1.26 (d, J = 6.1 Hz, 6 H); 2.25 (s, 3 H);A methylpyridin-3-yl)-2-{[4- 2.46 (masked m, 7 H); 3.07 (m, 4 H); 548(4-methylpiperazin-1-yl)- 3.77 (s, 3 H); 4.64 (spt, J = 6.0 Hz, 1 H);0.64 2-(propan-2- 6.35 (dd, J = 2.6 and 8.9 Hz, 1 H);yloxy)phenyl]amino}thieno[3, 6.62 (d, J = 2.4 Hz, 1 H); 7.01 (d, J = 7.6Hz, 1 2-d]pyrimidine-6- H); 7.33 (broad s, 1 H); 7.66 (broad s, 1carboxamide H); 7.78 (d, J = 7.3 Hz, 1 H); 7.82 (s, 1 H); 7.92 (d, J =8.8 Hz, 1 H); 9.16 (s, 1 H) I-122 II-47 IIIb-3 7-(2-Methoxy-6- 1.29 (d,J = 6.1 Hz, 6 H); 1.55 to 1.78 (m, A methylpyridin-3-yl)-2-{[4- 4 H);2.00 (t, J = 10.8 Hz, 2 H); 2.22 (s, 3 547 (1-methylpiperidin-4-yl)-2-H); 2.41 (m, 1 H); 2.50 (masked s, 3 H); 0.68 (propan-2- 2.89 (d, J =11.2 Hz, 2 H); 3.78 (s, 3 H); yloxy)phenyl]amino}thieno[3, 4.67 (spt, J= 6.0 Hz, 1 H); 6.65 (dd, 2-d]pyrimidine-6- J = 1.6 and 8.4 Hz, 1 H);6.89 (d, J = 1.5 Hz, carboxamide 1 H); 7.03 (d, J = 7.3 Hz, 1 H); 7.36(broad s, 1 H); 7.69 (broad s, 1 H); 7.80 (d, J = 7.3 Hz, 1 H); 7.91 (s,1 H); 8.11 (d, J = 8.3 Hz, 1 H); 9.22 (s, 1 H) I-123 II-19 IIIb-582-{[3-(1-Ethylpiperidin-4- 1.04 (t, J = 7.3 Hz, 3 H); 1.22 (d, J = 6.8Hz, A yl)-1-(propan-2-yl)-1H- 6 H); 1.48 (qd, J = 3.4 and 12.7 Hz, 2 572pyrazol-5-yl]amino}-7-[2- H); 1.73 (d, J = 11.7 Hz, 2 H); 1.93 (m, 20.61 (trifluoromethoxy)phenyl]thieno[3, H); 2.37 (m, 3 H); 2.90 (d, J =11.7 Hz, 2 2-d]pyrimidine-6- H); 4.47 (dt, J = 6.8 and 13.3 Hz, 1 H);carboxamide 5.98 (s, 1 H); 7.33 (broad s, 1 H); 7.46 (m, 2 H); 7.57 (m,2 H); 7.72 (broad s, 1 H); 9.25 (s, 1 H); 9.35 (s, 1 H) I-124 II-5IIIb-8 2-({4-[(3R,4S)-3-Hydroxy- ¹H NMR spectrum (500 MHz, d in ppm, A1-methylpiperidin-4-yl]-2- CHLOROFORM-d): 1.37 (d, J = 5.5 Hz, 6 548(propan-2- H); 1.65 (d, J = 11.0 Hz, 1 H); 2.06 (m, 1 0.64yloxy)phenyl}amino)-7-(2- H); 2.21 (m, 2 H); 2.32 (s, 3 H);methoxyphenyl)thieno[3,2- 2.36 (broad s, 1 H); 2.55 (d, J = 12.6 Hz, 1H); d]pyrimidine-6- 2.95 (d, J = 11.0 Hz, 1 H); 3.01 (d, carboxamide J =11.0 Hz, 1 H); 3.76 (s, 3 H); 3.87 (broad s, 1 H); 4.61 (dt, J = 6.0 and12.1 Hz, 1 H); 5.49 (broad s, 1 H); 6.03 (broad s, 1 H); 6.64 (d, J =8.5 Hz, 1 H); 6.88 (s, 1 H); 7.11 (d, J = 8.2 Hz, 1 H); 7.18 (t, J = 7.4Hz, 1 H); 7.47 (d, J = 7.7 Hz, 1 H); 7.54 (t, J = 7.8 Hz, 1 H); 7.86 (s,1 H); 8.31 (d, J = 8.2 Hz, 1 H); 8.97 (s, 1 H) I-125 II-31 IIIb-207-(2-Methoxypyridin-3-yl)- 1.24 (m, J = 6.1 Hz, 7 H); 1.35 to A2-({4-[(8S,8aS)- 1.80 (m, 7 H); 1.91 (td, J = 6.1 and 9.8 Hz, 1 559octahydroindolizin-8-yl]-2- H); 2.07 (m, 2 H); 2.31 (m, 1 H); 0.67(propan-2- 3.01 (m, 2 H); 3.80 (s, 3 H); 4.67 (spt, J = 6.0 Hz,yloxy)phenyl}amino)thieno[3, 1 H); 6.62 (dd, J = 1.5 and 8.3 Hz, 12-d]pyrimidine-6- H); 6.87 (d, J = 1.5 Hz, 1 H); 7.18 (dd, carboxamide J= 5.1 and 7.3 Hz, 1 H); 7.47 (broad s, 1 H); 7.69 (broad s, 1 H); 7.91(dd, J = 2.0 and 7.3 Hz, 1 H); 7.93 (s, 1 H); 8.08 (d, J = 8.3 Hz, 1 H);8.28 (dd, J = 2.0 and 5.1 Hz, 1 H); 9.24 (s, 1 H) I-126 II-31 IIIb-207-(2-Methoxypyridin-3-yl)- 1.25 to 1.34 (m, 6 H); 1.39 to 1.74 (m, 8 A2-({4-[(8R,8aS)- H); 1.96 (m, 2 H); 2.21 (broad s, 1 H); 559octahydroindolizin-8-yl]-2- 3.00 (d, J = 16.9 Hz, 2 H); 3.12 (d, 0.68(propan-2- J = 10.0 Hz, 1 H); 3.79 (s, 3 H); 4.52 (spt,yloxy)phenyl}amino)thieno[3, J = 6.0 Hz, 1 H); 6.84 (d, J = 8.1 Hz, 1H); 2-d]pyrimidine-6- 7.14 (dd, J = 5.0 and 7.2 Hz, 1 H); carboxamide7.47 (broad s, 1 H); 7.53 (broad s, 1 H); 7.69 (broad s, 1 H); 7.90 (m,2 H); 8.03 (d, J = 8.3 Hz, 1 H); 8.26 (dd, J = 2.0 and 4.9 Hz, 1 H);9.23 (s, 1 H) I-127 II-5 IIIb-49 7-(2-Methoxyphenyl)-2- 1.33 (d, J = 5.9Hz, 6 H); 3.72 (s, 3 H); A {[4-(1-methyl-1H-pyrazol- 3.85 (s, 3 H); 4.78(spt, J = 6.0 Hz, 1 H); 484 4-yl)-2-(propan-2- 6.92 (d, J = 6.8.Hz, 2H); 7.19 (m, 3 H); 0.97 yloxy)phenyl]amino}thieno[3, 7.51 (m, 2 H); 7.74(broad s, 1 H); 2-d]pyrimidine-6- 7.81 (s, 1 H); 7.92 (s, 1 H); 8.08 (s,1 H); carboxamide 8.23 (d, J = 8.6 Hz, 1 H); 9.24 (s, 1 H) I-128 II-31IIIb-52 7-(2-Methoxypyridin-3-yl)- 1.99 (m, 2 H); 2.13 (m, 2 H); 2.55(t, A 2-[(1-methyl-2-oxo- J = 6.8 Hz, 2 H); 2.97 (s, 3 H); 3.77 (s, 3475 2,3,4,5-tetrahydro-1H-1- H); 7.06 (m, 2 H); 7.38 (m, 2 H); 0.70benzazepin-8- 7.67 (broad s, 1 H); 7.75 (s, 1 H); 7.86 (m, 1yl)amino]thieno[3,2- H); 8.22 (d, J = 4.9 Hz, 1 H); 9.27 (s, 1d]pyrimidine-6- H); 9.75 (s, 1 H) carboxamide I-129 II-31 IIIb-387-(2-Methoxypyridin-3-yl)- 1.32 (d, J = 6.4 Hz, 6 H); 2.27 (s, 3 H); A2-{[4-(2-methyl-1H- 3.80 (s, 3 H); 4.77 (spt, J = 6.1 Hz, 1 H); 561imidazol-1-yl)-2-(propan- 6.79 (dd, J = 2.0 and 8.8 Hz, 1 H); 0.63 2-6.88 (s, 1 H); 7.10 (s, 1 H); 7.19 (dd, J = 4.9yloxy)phenyl]amino}thieno[3, and 7.3 Hz, 1 H); 7.22 (s, 1 H);2-d]pyrimidine-6- 7.48 (broad s, 1 H); 7.70 (broad s, 1 H); carboxamide7.93 (d, J = 7.3 Hz, 1 H); 8.12 (s, 1 H); 8.25 (d, J = 4.9 Hz, 1 H);8.34 (d, J = 8.8 Hz, 1 H); 9.30 (s, 1 H) I-130 II-5 IIIb-172-{[5-Fluoro-4-(1- 1.29 (d, J = 6.0 Hz, 6 H); 1.54 to 1.81 (m, Amethylpiperidin-4-yl)-2- 4 H); 1.95 (m, 2 H); 2.19 (s, 3 H); 550(propan-2- 2.63 (m, 1 H); 2.85 (d, J = 11.3 Hz, 2 H); 0.71yloxy)phenyl]amino}-7-(2- 3.71 (s, 3 H); 4.65 (spt, J = 6.2 Hz, 1 H);methoxyphenyl)thieno[3,2- 6.89 (d, J = 6.8 Hz, 1 H); 6.95 (broad s, 1H); d]pyrimidine-6- 7.11 (t, J = 7.5 Hz, 1 H); 7.19 (d, J = 8.1 Hz,carboxamide 1 H); 7.49 (m, 2 H); 7.77 (broad s, 1 H); 7.93 (s, 1 H);8.14 (d, J = 13.2 Hz, 1 H); 9.27 (s, 1 H) I-131 II-31 IIIb-172-{[5-Fluoro-4-(1- 1.30 (d, J = 5.9 Hz, 6 H); 1.59 to 1.81 (m, Amethylpiperidin-4-yl)-2- 4 H); 1.94 (m, 2 H); 2.19 (s, 3 H); 551(propan-2- 2.66 (m, 1 H); 2.85 (d, J = 11.2 Hz, 2 H); 0.56yloxy)phenyl]amino}-7-(2- 3.81 (s, 3 H); 4.65 (spt, J = 6.0 Hz, 1 H);methoxypyridin-3- 6.90 (d, J = 7.1 Hz, 1 H); 7.14 (dd, J = 4.9 andyl)thieno[3,2-d]pyrimidine- 7.3 Hz, 1 H); 7.49 (broad s, 1 H);6-carboxamide 7.72 (broad s, 1 H); 7.93 (dd, J = 1.8 and 7.2 Hz, 1 H);7.97 (s, 1 H); 8.11 (d, J = 13.0 Hz, 1 H); 8.28 (dd, J = 1.8 and 5.0 Hz,1 H); 9.29 (s, 1 H) I-132 II-31 IIIb-39 7-(2-Methoxypyridin-3-yl)- 1.30(d, J = 6.0 Hz, 6 H); 1.79 (s, 3 H); A 2-{[5-methyl-4-(2-methyl- 2.08(s, 3 H); 3.80 (s, 3 H); 4.70 (m, 1 530 1H-imidazol-1-yl)-2- H); 6.89(s, 1 H); 6.98 (s, 1 H); 7.08 (s, 0.66 (propan-2- 1 H); 7.18 (m, 1 H);7.49 (s, 1 H); yloxy)phenyl]amino}thieno[3, 7.73 (s, 1 H); 7.92 (d, J =7.3 Hz, 1 H); 2-d]pyrimidine-6- 8.03 (s, 1 H); 8.25 (d, J = 5.0 Hz, 1H); carboxamide 8.30 (s, 1 H); 9.30 (s, 1 H) I-133 II-5 IIIb-427-(2-Methoxyphenyl)-2- 1.35 (d, J = 6.0 Hz, 6 H); 3.71 (s, 3 H); A{[2-(propan-2-yloxy)-4- 4.81 (m, 1 H); 6.85 (broad s, 1 H); 7.12 502(1H-1,2,4-triazol-1- to 7.25 (m, 3 H); 7.45 to 7.55 (m, 3 H); 0.91yl)phenyl]amino}thieno[3, 7.78 (broad s, 1 H); 8.07 (s, 1 H);2-d]pyrimidine-6- 7.19 (s, 1 H); 8.42 (d, J = 8.0 Hz, 1 H); carboxamide9.22 (s, 1 H); 9.29 (s, 1 H) I-134 II-5 IIIb-60 7-(2-Methoxyphenyl)-2-3.78 (s, 3 H); 6.31 (d, J = 1.9 Hz, 1 H); A [(1-phenyl-1H-pyrazol-5-6.24 (broad s, 1 H); 7.05 (t, J = 7.7 Hz, 443 yl)amino]thieno[3,2- 1 H);7.12 (d, J = 8.0 Hz, 1 H); 8.26 (m, 0.76 d]pyrimidine-6- 2 H); 7.38 (t,J = 7.6 Hz, 2 H); 7.44 (m, carboxamide 3 H); 7.59 (d, J = 1.9 Hz, 1 H);7.71 (broad s, 1 H); 9.10 (s, 1 H); 9.29 (broad s, 1 H) I-135 II-5IIIb-50 7-(2-Methoxyphenyl)-2- 1.35 (d, J = 6.0 Hz, 6 H); 3.71 (s, 3 H);A {[4-(1-methyl-1H-pyrazol- 3.88 (s, 3 H); 4.75 (m, 1 H); 6.63 (d, J =1.9 Hz, 515 3-yl)-2-(propan-2- 1 H) 6.92 (broad s, 1 H); 1.0yloxy)phenyl]amino}thieno[3, 7.16 (m, 2 H); 7.22 (d, J = 8.0 Hz, 1 H);2-d]pyrimidine-6- 7.39 (d, J = 1.7 Hz, 1 H); 7.48 to 7.56 (m, 2carboxamide H); 7.69 (d, J = 1.9 Hz, 1 H); 7.75 (broad s, 1 H); 7.98 (s,1 H); 8.30 (d, J = 8.5 Hz, 1 H); 9.26 (s, 1 H) I-136 II-31 IIIb-647-(2-Methoxypyridin-3-yl)- 1.22 (d, J = 6.0 Hz, 6 H); 2.09 (s, 3 H); A2-{[3-methyl-1-(propan-2- 3.78 (s, 3 H); 4.45 (m, 1 H); 5.93 (s, 1 424yl)-1H-pyrazol-5- H); 7.10 (dd, J = 5.0 and 7.2 Hz, 1 H); 0.58yl]amino}thieno[3,2- 7.39 (broad m, 1 H); 7.69 (broad m, 1d]pyrimidine-6- H); 7.80 (dd, J = 2.2 and 7.2 Hz, 1 H); carboxamide 8.22(dd, J = 2.2 and 5.0 Hz, 1 H); 9.21 (s, 1 H); 9.32 (s, 1 H) I-137 II-16IIIb-7 7-(2-Fluorophenyl)-2-{[5- 1.29 (d, J = 6.0 Hz, 6 H); 1.53 to Bmethyl-4-(1- 1.70 (m, 4 H); 1.97 (m, 2 H); 2.08 (s, 3 H); 534methylpiperidin-4-yl)-2- 2.20 (s, 3 H); 2.52 (partially masked m, 0.83(propan-2- 1 H); 2.85 (m, 2 H); 4.62 (m, 1 H);yloxy)phenyl]amino}thieno[3, 6.80 (s, 1 H); 7.35 (m, 2 H); 7.48 to 7.67(m, 2-d]pyrimidine-6- 3 H); 7.78 (broad m, 1 H); 7.88 (s, 1 H);carboxamide 8.02 (s, 1 H); 9.28 (s, 1 H) I-138 II-5 IIIb-527-(2-Methoxyphenyl)-2- 1.99 (m, 2 H); 2.11 (t, J = 6.9 Hz, 2 H); B[(1-methyl-2-oxo-2,3,4,5- 2.52 (t, J = 6.9 Hz, 2 H); 2.72 (s, 3 H); 474tetrahydro-1H-1- 3.68 (s, 3 H); 6.72 (broad m, 1 H); 1.01 benzazepin-8-7.05 (m, 2 H); 7.15 (d, J = 8.5 Hz, 1 H); yl)amino]thieno[3,2- 7.38 (dd,J = 2.5 and 8.5 Hz, 1 H); 7.40 to d]pyrimidine-6- 7.49 (m, 2 H); 7.73(broad m, 1 H); carboxamide 7.79 (d, J = 2.5 Hz, 1 H); 9.23 (s, 1 H);9.73 (s, 1 H) I-139 II-10 IIIb-59 7-(4-Fluoro-2- 1.21 (broad d, J = 6.0Hz, 6 H); 1.30 to B methoxyphenyl)-2-{[3- 1.53 (m, 2 H); 1.63 (m, 1 H);1.88 (m, 1 510 (piperidin-3-yl)-1-(propan- H); 2.40 to 2.60 (partiallymasked m, 3 0.74 2-yl)-1H-pyrazol-5- H); 2.90 to 3.08 (m, 2 H); 3.58(broad yl]amino}thieno[3,2- m, 1 H); 3.68 (s, 3 H); 4.52 (m, 1 H);d]pyrimidine-6- 6.00 (s, 1 H); 6.89 (dt, J = 2.5 and 8.5 Hz, carboxamide1 H); 6.93 (broad m, 1 H); 7.04 (dd, J = 2.5 and 11.4 Hz, 1 H); 7.39(dd, J = 7.1 and 8.5 Hz, 1 H); 7.72 (broad m, 1 H); 9.21 (s, 1 H); 9.39(broad s, 1 H) I-140 II-31 IIIb-63 2-{[3-Cyclopropyl-1- 0.49 (m, 2 H);0.80 (m, 2 H); 1.22 (d, J = 6.0 Hz, B (propan-2-yl)-1H-pyrazol- 6 H);1.78 (m, 1 H); 3.78 (s, 3 450 5-yl]amino}-7-(2- H); 4.49 (m, 1 H); 5.79(s, 1 H); 0.92 methoxypyridin-3- 7.10 (dd, J = 5.0 and 7.3 Hz, 1 H);yl)thieno[3,2-d]pyrimidine- 7.38 (broad m, 1 H); 7.70 (broad m, 1 H);6-carboxamide 7.79 (dd, J = 2.0 and 7.3 Hz, 1 H); 8.23 (dd, J = 2.0 and5.0 Hz, 1 H); 9.21 (s, 1 H); 9.31 (broad s, 1 H) I-141 II-10 IIIb-627-(4-Fluoro-2- 1.33 (d, J = 6.0 Hz, 6 H); 3.68 (s, 3 H); Bmethoxyphenyl)-2-{[1- 4.69 (m, 1 H); 6.71 (s, 1 H); 6.89 (dt, J = 2.9504 (propan-2-yl)-3-(pyridin-3- and 8.8 Hz, 1 H); 6.97 (broad m, 1 0.86yl)-1H-pyrazol-5- H); 7.05 (dd, J = 2.9 and 11.9 Hz, 1 H);yl]amino}thieno[3,2- 7.39 to 7.49 (m, 2 H); 7.73 (broad m, 1d]pyrimidine-6- H); 7.99 (td, J = 1.7 and 7.5 Hz, 1 H); carboxamide 8.50(dd, J = 1.7 and 5.0 Hz, 1 H); 8.90 (d, J = 1.7 Hz, 1 H); 9.27 (s, 1 H);9.65 (broad s, 1 H) I-142 II-31 IIIb-53 7-(2-Methoxypyridin-3-yl)- 2.00(m, 2 H); 2.11 (m, 2 H); B 2-[(1-methyl-2-oxo- 2.48 (partially masked m,2 H); 3.28 (s, 3 H); 475 2,3.4,5-tetrahydro-1H-1- 3.80 (s, 3 H); 7.12(d, J = 8.8 Hz, 1 H); 0.88 benzazepin-7- 7.18 (dd, J = 5.0 and 7.3 Hz, 1H); yl)amino]thieno[3,2- 6.91 (broad m, 1 H); 7.48 (dd, J = 2.6 andd]pyrimidine-6- 8.8 Hz, 1 H); 7.71 (broad m, 1 H); carboxamide 7.82 (d,J = 2.6 Hz, 1 H); 7.90 (dd, J = 1.8 and 7.3 Hz, 1 H); 8.28 (dd, J = 1.8and 5.0 Hz, 1 H); 9.28 (s, 1 H); 9.80 (broad s, 1 H) I-143 II-10 IIIb-427-(4-Fluoro-2- 1.35 (d, J = 6.0 Hz, 6 H); 3.72 (s, 3 H); Bmethoxyphenyl)-2-{[2- 4.73 (m, 1 H); 6.99 (m, 1 H); 7.08 to 520(propan-2-yloxy)-4-(1H- 7.19 (m, 2 H); 7.28 (d, J = 8.5 Hz, 1 H); 1.191,2,4-triazol-1- 7.51 (m, 2 H); 7.73 (s, 1 H); 8.09 (s, 1yl)phenyl]amino}thieno[3, H); 8.20 (s, 1 H); 8.42 (d, J = 8.5 Hz, 12-d]pyrimidine-6- H); 9.22 (s, 1 H); 9.29 (s, 1 H) carboxamide I-144II-31 IIIb-41 2-{[4-(2,4-Dimethyl-1H- 1.30 (d, J = 6.0 Hz, 6 H); 2.09(s, 3 H); B imidazol-1-yl)-2-(propan- 2.21 (s, 3 H); 3.80 (s, 3 H); 4.75(m, 1 530 2-yloxy)phenyl]amino}-7- H); 6.76 (d, J = 8.5 Hz, 1 H); 6.90(s, 1 0.89 (2-methoxypyridin-3- H); 7.05 (s, 1 H); 7.20 (m, 1 H);yl)thieno[3,2-d]pyrimidine- 7.49 (broad m, 1 H); 7.70 (broad m, 1 H);6-carboxamide 7.92 (m, 1 H); 8.10 (s, 1 H); 8.25 (m, 1 H); 8.30 (d, J =8.5 Hz, 1 H); 9.30 (s, 1 H) I-145 II-31 IIIb-51 2-{[4-Methoxy-2-(propan-1.28 (d, J = 6.0 Hz, 6 H); 3.71 (s, 3 H); B 2-yloxy)phenyl]amino}-7-3.80 (s, 3 H); 4.63 (m, 1 H); 6.35 (broad 466 (2-methoxypyridin-3- d, J= 8.5 Hz, 1 H); 6.61 (broad s, 1 H); 1.26 yl)thieno[3,2-d]pyrimidine-7.17 (m, 1 H); 7.43 (broad m, 1 H); 6-carboxamide 7.68 (broad m, 1 H);7.88 (m, 2 H); 7.97 (d, J = 8.5 Hz, 1 H); 8.25 (d, J = 5.0 Hz, 1 H);9.19 (s, 1 H) I-146 II-5 IIIb-61 2-[(3-Cyclopropyl-1- 0.61 (m, 2 H);0.89 (m, 2 H); 1.36 (m, 1 B phenyl-1H-pyrazol-5- H); 3.68 (s, 3 H); 6.04(s, 1 H); 483 yl)amino]-7-(2- 6.75 (broad m, 1 H); 7.08 (t, J = 7.8 Hz,1 H); 1.17 methoxyphenyl)thieno[3,2- 7.24 (d, J = 8.0 Hz, 1 H); 7.27(tt, J = 1.7 d]pyrimidine-6- and 7.5 Hz, 1 H); 7.29 (dd, J = 2.0carboxamide and 8.0 Hz, 1 H); 7.37 (t, J = 7.8 Hz, 2 H); 7.45 (m, 3 H);7.71 (broad m, 1 H); 9.11 (s, 1 H); 9.22 (broad s, 1 H) I-147 II-31IIIb-29 2-{[4-(5,6- 1.29 (d, J = 6.0 Hz, 6 H); 3.61 (m, 2 H); BDihydroimidazo[1,2- 3.80 (s, 3 H); 4.08 (m, 2 H); 4.31 (s, 2 557a]pyrazin-7(8H)-yl)-2- H); 4.72 (m, 1 H); 6.48 (dd, J = 3.0 and 0.84(propan-2- 8.9 Hz, 1 H); 6.79 (d, J = 3.0 Hz, 1 H);yloxy)phenyl]amino}-7-(2- 6.90 (d, J = 10 Hz, 1 H); 7.10 (d, J = 1.0 Hz,methoxypyridin-3- 1 H); 7.19 (dd, J = 5.0 and 7.3 Hz, 1yl)thieno[3,2-d]pyrimidine- H); 7.46 (broad m, 1 H); 7.69 (broad m,6-carboxamide 1 H); 7.88 (s, 1 H); 7.90 (dd, J = 2.0 and 7.3 Hz, 1 H);8.00 (d, J = 8.9 Hz, 1 H); 8.28 (dd, J = 2.0 and 5.0 Hz, 1 H); 9.20 (s,1 H) I-148 II-5 IIIb-6 2-{[4-(1- 0.30 (m, 2 H); 0.42 (m, 2 H); 1.29 (d,J = 6.0 Hz, B Cyclopropylpiperidin-4- 6 H); 1.48 to 1.72 (m, 5 H); 558yl)-2-(propan-2- 2.21 (m, 2 H); 2.41 (m, 1 H); 3.00 (m, 2 0.95yloxy)phenyl]amino}-7-(2- H); 3.70 (s, 3 H); 4.68 (m, 1 H);methoxyphenyl)thieno[3,2- 6.59 (dd, J = 1.7 and 8.6 Hz, 1 H); 6.86 (d, J= 1.7 Hz, d]pyrimidine-6- 1 H); 6.90 (broad m, 1 H); carboxamide 7.13(t, J = 7.8 Hz, 1 H); 7.20 (d, J = 8.0 Hz, 1 H); 7.42 to 7.52 (m, 2 H);7.74 (broad m, 1 H); 7.86 (s, 1 H); 8.12 (d, J = 8.6 Hz, 1 H); 9.20 (s,1 H) I-149 II-11 IIIb-6 2-{[4-(1- 0.30 (m, 2 H); 0.42 (m, 2 H); 1.29 (d,J = 6.0 Hz, B Cyclopropylpiperidin-4- 6 H); 1.48 to 1.72 (m, 5 H); 576yl)-2-(propan-2- 2.21 (m, 2 H); 2.42 (m, 1 H); 3.00 (m, 2 0.96yloxy)phenyl]amino}-7-(5- H); 3.69 (s, 3 H); 4.68 (m, 1 H); fluoro-2-6.60 (dd, J = 1.7 and 8.6 Hz, 1 H); 6.89 (d, J = 1.7 Hz,methoxyphenyl)thieno[3,2- 1 H); 7.15 (dd, J = 4.5 and 9.2 Hz,d]pyrimidine-6- 1 H); 7.24 (broad m, 1 H); 7.30 (dt, carboxamide J = 3.0and 9.02 Hz, 1 H); 7.38 (dd, J = 3.0 and 9.4 Hz, 1 H); 7.70 (broad m, 1H); 7.90 (s, 1 H); 8.15 (d, J = 8.6 Hz, 1 H); 9.21 (s, 1 H) I-150 II-31IIIb-6 2-{[4-(1- 0.30 (m, 2 H); 0.42 (m, 2 H); 1.29 (d, J = 6.0 Hz, BCyclopropylpiperidin-4- 6 H); 1.48 to 1.72 (m, 5 H); 559yl)-2-(propan-2- 2.22 (m, 2 H); 2.42 (m, 1 H); 3.01 (m, 2 0.89yloxy)phenyl]amino}-7-(2- H); 3.80 (s, 3 H); 4.68 (m, 1 H);methoxypyridin-3- 6.61 (dd, J = 1.7 and 8.4 Hz, 1 H); 6.89 (d, J = 1.7Hz, yl)thieno[3,2-d]pyrimidine- 1 H); 7.19 (dd, J = 4.9 and 7.4 Hz,6-carboxamide 1 H); 7.48 (broad m, 1 H); 7.70 (broad m, 1 H); 7.81 (m, 2H); 8.10 (d, J = 8.4 Hz, 1 H); 8.29 (dd, J = 1.9 and 4.9 Hz, 1 H); 9.22(s, 1 H) I-151 II-31 IIIb-40 7-(2-Methoxypyridin-3-yl)- 1.32 (d, J = 6.0Hz, 6 H); 2.25 (s, 3 H); B 2-{[4-(4-methyl-1H- 3.80 (s, 3 H); 3.83 (m, 1H); 6.98 (dd, J = 2.1 516 imidazol-1-yl)-2-(propan- and 8.7 Hz, 1 H);7.21 (dd, J = 5.0 0.87 2- and 7.5 Hz, 1 H); 8.24 (d, J = 2.1 Hz, 1yloxy)phenyl]amino}thieno[3, H); 7.40 (s, 1 H); 7.50 (broad m, 1 H);2-d]pyrimidine-6- 7.71 (broad m, 1 H); 7.92 (dd, J = 1.9 carboxamide and7.5 Hz, 1 H); 8.08 (s, 2 H); 8.28 (m, 2 H); 9.29 (s, 1 H) I-152 II-10IIIb-53 7-(4-Fluoro-2- 2.00 (m, 2 H); 2.10 (m, 2 H); 2.48 (m, 2 Bmethoxyphenyl)-2-[(1- H); 3.18 (s, 3 H); 3.70 (s, 3 H); 6.90 to 492methyl-2-oxo-2,3,4,5- 7.16 (m, 4 H); 7.48 (m, 2 H); 0.99tetrahydro-1H-1- 7.72 (broad m, 1 H); 7.82 (d, J = 2.1 Hz, 1benzazepin-7- H); 9.22 (s, 1 H); 9.78 (s, 1 H) yl)amino]thieno[3,2-d]pyrimidine-6- carboxamide I-153 II-30 IIIb-252-{[4-(4-Methylpiperazin- 1.25 (d, J = 6.0 Hz, 6 H); 2.21 (s, 3 H); B1-yl)-2-(propan-2- 2.43 (m, 4 H); 3.05 (m, 4 H); 4.65 (m, 1 520yloxy)phenyl]amino}-7-(1- H); 6.40 (dd, J = 2.2 and 9.0 Hz, 1 H); 0.68oxidopyridin-2- 6.60 (d, J = 2.1 Hz, 1 H); 7.62 (m, 2 H);yl)thieno[3,2-d]pyrimidine- 7.76 (m, 2 H); 7.80 (d, J = 9.0 Hz, 1 H);6-carboxamide 7.89 (s, 1 H); 8.50 (m, 1 H); 9.00 (broad m, 1 H); 9.29(s, 1 H) I-154 II-5 IIIb-46 2-{[4-(1-Ethyl-1,7- 1.02 (t, J = 7.0 Hz, 3H); 1.23 (d, J = 6.0 Hz, B diazaspiro[4.4]non-7-yl)- 6 H); 1.64 (m, 1H); 1.76 (m, 4 H); 587 2-(propan-2- 2.08 (m, 1 H); 2.40 to 2.65(partially 0.96 yloxy)phenyl]amino}-7-(2- masked m, 3 H); 2.82 (m, 1 H);2.92 (d, methoxyphenyl)thieno[3,2- J = 9.3 Hz, 1 H); 3.10 to 3.38(partially d]pyrimidine-6- masked m, 3 H); 3.70 (s, 3 H); 4.61 (m,carboxamide 1 H); 5.92 (dd, J = 2.1 and 9.0 Hz, 1 H); 6.19 (d, J = 2.1Hz, 1 H); 6.82 (broad m, 1 H); 7.11 (t, J = 7.8 Hz, 1 H); 7.19 (d, J =8.0 Hz, 1 H); 7.41 to 7.51 (m, 2 H); 7.70 (m, 2 H); 7.82 (d, J = 9.0 Hz,1 H); 9.10 (s, 1 H) I-155 II-44 IIIb-26 7-(2-Ethoxypyridin-3-yl)- 1.08(t, J = 7.0 Hz, 3 H); 1.29 (d, J = 6.0 Hz, B 2-{[5-methyl-4-(4- 6 H);2.03 (s, 3 H); 2.22 (s, 3 H); 562 methylpiperazin-1-yl)-2- 2.45 (m, 4H); 2.79 (m, 4 H); 4.29 (q, J = 7.0 Hz, 0.88 (propan-2- 2 H); 4.60 (m, 1H); 6.70 (s, 1 yloxy)phenyl]amino}thieno[3, H); 7.13 (dd, J = 5.1 and7.4 Hz, 1 H); 2-d]pyrimidine-6- 7.47 (broad m, 1 H); 7.70 (broad m, 1carboxamide H); 7.81 (s, 1 H); 7.92 (dd, J = 2.1 and 7.4 Hz, 1 H); 8.03(s, 1 H); 8.23 (dd, J = 2.1 and 5.1 Hz, 1 H); 9.21 (s, 1 H) I-156 II-5IIIb-67 2-{[4-(3,5-Dimethyl-1H- 1.31 (d, J = 6.0 Hz, 6 H); 2.25 (s, 3H); B 1,2,4-triazol-1-yl)-2- 2.39 (s, 3 H); 3.70 (s, 3 H); 4.76 (m, 1530 (propan-2- H); 6.85 (dd, J = 2.1 and 8.8 Hz, 1 H); 1.13yloxy)phenyl]amino}-7-(2- 6.95 (broad m, 1 H); 7.13 (t, J = 7.8 Hz,methoxyphenyl)thieno[3,2- 1 H); 7.19 (d, J = 2.1 Hz, 1 H); 7.20 (d,d]pyrimidine-6- J = 8.0 Hz, 1 H); 7.49 (m, 2 H); carboxamide 7.78 (broadm, 1 H); 8.09 (s, 1 H); 8.40 (d, J = 8.8 Hz, 1 H); 9.29 (s, 1 H) I-157II-36 IIIb-26 7-(5-Fluoro-2- 1.28 (d, J = 6.1 Hz, 6 H); 2.05 (s, 3 H); Bmethoxypyridin-3-yl)-2- 2.23 (s, 3 H); 2.46 (m, 4 H); 2.78 (m, 4 566{[5-methyl-4-(4- H); 3.78 (s, 3 H); 4.60 (m, 1 H); 6.70 (s, 0.88methylpiperazin-1-yl)-2- 1 H); 7.55 to 7.74 (broad m, 2 H); 7.86(propan-2- to 7.94 (m, 2 H); 7.98 (s, 1 H); 8.25 (d,yloxy)phenyl]amino}thieno[3, J = 3.1 Hz, 1 H); 9.23 (s, 1 H)2-d]pyrimidine-6- carboxamide I-158 II-47 IIIb-38 7-(2-Methoxy-6- 1.31(d, J = 6.0 Hz, 6 H); 2.29 (s, 3 H); B methylpyridin-3-yl)-2-{[4- 2.47(s, 3 H); 3.79 (s, 3 H); 4.79 (m, 1 530 (2-methyl-1H-imidazol-1- H);6.81 (dd, J = 2.2 and 8.6 Hz, 1 H); 0.89 yl)-2-(propan-2- 6.90 (d, J =1.0 Hz, 1 H); 7.04 (d, J = 7.6 Hz, yloxy)phenyl]amino}thieno[3, 1 H);7.11 (d, J = 2.1 Hz, 1 H); 2-d]pyrimidine-6- 7.22 (d, J = 1.0 Hz, 1 H);7.40 (broad m, carboxamide 1 H); 7.70 (broad m, 1 H); 7.81 (d, J = 7.6Hz, 1 H); 8.11 (s, 1 H); 8.36 (d, J = 8.6 Hz, 1 H); 9.29 (s, 1 H) I-159II-5 IIIb-66 7-(2-Methoxyphenyl)-2- 1.30 (d, J = 6.0 Hz, 6 H); 2.13 (s,3 H); B ({4-[(4-methylpiperazin-1- 2.30 (broad m, 8 H); 3.38 (s, 2 H);547 yl)methyl]-2-(propan-2- 3.70 (s, 3 H); 4.61 (m, 1 H); 6.82 (dd, J =1.9 0.82 yloxy)phenyl}amino)thieno[3, and 8.8 Hz, 1 H); 6.89 (broad m, 1H); 2-d]pyrimidine-6- 6.91 (d, J = 1.9 Hz, 1 H); 7.11 (t, J = 7.8 Hz,carboxamide 1 H); 7.19 (d, J = 8.0 Hz, 1 H); 7.42 to 7.52 (m, 2 H); 7.71(broad m, 1 H); 7.90 (s, 1 H); 8.17 (d, J = 8.8 Hz, 1 H); 9.21 (s, 1 H)I-160 II-47 IIIb-26 7-(2-Methoxy-6- 1.30 (d, J = 6.0 Hz, 6 H); 2.03 (s,3 H); B methylpyridin-3-yl)-2-{[5- 2.22 (s, 3 H); 2.40 to 2.53(partially 562 methyl-4-(4- masked m, 7 H); 2.79 (m, 4 H); 3.78 (s, 0.89methylpiperazin-1-yl)-2- 3 H); 4.60 (m, 1 H); 6.70 (s, 1 H); (propan-2-7.01 (d, J = 7.7 Hz, 1 H); 7.30 (broad m, 1 yloxy)phenyl]amino}thieno[3,H); 7.70 (broad m, 1 H); 7.78 (d, J = 7.7 Hz, 2-d]pyrimidine-6- 1 H);7.80 (s, 1 H); 8.03 (s, 1 H); carboxamide 9.20 (s, 1 H) I-161 II-5IIIb-65 7-(2-Methoxyphenyl)-2- 1.22 (d, J = 6.0 Hz, 6 H); 2.04 (m, 2 H);B {[1-methyl-2-oxo-6- 2.16 (m, 2 H); 2.69 (m, 2 H); 3.20 (s, 3 532(propan-2-yloxy)-2,3,4,5- H); 3.70 (s, 3 H); 4.18 (m, 1 H); 6.90 (m,1.18 tetrahydro-1H-1- 2 H); 7.11 (t, J = 8.0 Hz, 1 H); 7.19 (d, J = 8.0Hz, benzazepin-7- 1 H); 7.48 (m, 2 H); yl]amino}thieno[3,2- 7.72 (broadm, 1 H); 8.03 (d, J = 8.0 Hz, 1 d]pyrimidine-6- H); 8.13 (s, 1 H); 9.22(s, 1 H) carboxamide I-162 II-31 IIIb-65 7-(2-Methoxypyridin-3-yl)- 1.21(d, J = 6.0 Hz, 6 H); 2.04 (m, 2 H); B 2-{[1-methyl-2-oxo-6- 2.17 (m, 2H); 2.69 (m, 2 H); 3.20 (s, 3 533 (propan-2-yloxy)-2,3,4,5- H); 3.70 (s,3 H); 4.16 (m, 1 H); 6.95 (d, 1.09 tetrahydro-1H-1- J = 8.8 Hz, 1 H);7.18 (dd, J = 5.0 and benzazepin-7- 7.3 Hz, 1 H); 7.48 (broad m, 1 H);yl]amino}thieno[3,2- 7.70 (broad m, 1 H); 7.91 (dd, J = 2.0 andd]pyrimidine-6- 7.3 Hz, 1 H); 8.00 (d, J = 8.8 Hz, 1 H); carboxamide8.23 (m, 2 H); 9.26 (s, 1 H) I-163 II-5 IIIb-68 7-(2-Methoxyphenyl)-2-1.28 (d, J = 6.1 Hz, 6 H); 2.24 (s, 3 H); B {[5-(4-methylpiperazin-1-2.34 (m, 4 H); 2.68 (m, 4 H); 3.68 (s, 3 533 yl)-2-(propan-2- H); 4.49(m, 1 H); 6.43 (dd, J = 2.9 and 0.93 yloxy)phenyl]amino}thieno[3, 9.0Hz, 1 H); 6.64 (broad s, 1 H); 2-d]pyrimidine-6- 6.89 (d, J = 9.0 Hz, 1H); 7.09 (broad t, J = 7.8 Hz, carboxamide 1 H); 7.19 (broad d, J = 7.8Hz, 1 H); 7.38 (dd, J = 1.8 and 7.8 Hz, 1 H); 7.48 (m, 1 H); 7.74 (d, J= 2.9 Hz, 1 H); 7.78 (broad s, 1 H); 7.92 (s, 1 H); 9.26 (s, 1 H) I-164II-5 IIIb-69 7-(2-Methoxyphenyl)-2- 1.24 (d, J = 6.1 Hz, 6 H); 1.33 (m,2 H); B {[2-(propan-2-yloxy)-4- 1.85 (m, 2 H); 3.41 (m, 3 H); 3.70 (s, 3534 (tetrahydro-2H-pyran-4- H); 3.86 (m, 2 H); 4.49 (m, 1 H); 0.98ylamino)phenyl]amino}thieno[3, 5.17 (broad d, J = 8.3 Hz, 1 H); 6.03(dd, 2-d]pyrimidine-6- J = 2.5 and 8.5 Hz, 1 H); 6.31 (d, J = 2.5 Hz,carboxamide 1 H); 6.82 (broad s, 1 H); 7.09 (t, J = 7.8 Hz, 1 H); 7.15(d, J = 7.8 Hz, 1 H); 7.40 to 7.50 (m, 2 H); 7.65 to 7.75 (m, 3 H); 9.10(s, 1 H) I-165 II-48 IIIb-26 7-(3-Methoxypyridin-2-yl)- 1.28 (m, 6 H);2.00 (s, 3 H); 2.23 (s, 3 B 2-{[5-methyl-4-(4- H); 2.50 (masked m, 4 H);2.77 (m, 4 548 methylpiperazin-1-yl)-2- H); 3.70 (s, 3 H); 4.59 (m, 1H); 6.68 (s, 0.82 (propan-2- 1 H); 7.49 to 7.97 (m, 6 H); 8.35 (m, 1yloxy)phenyl]amino}thieno[3, H); 9.23 (s, 1 H) 2-d]pyrimidine-6-carboxamide I-166 II-31 IIIb-70 2-{[4-(4-Hydroxypiperidin- 1.26 (d, J =6.1 Hz, 6 H); 1.49 (m, 2 H); B 1-yl)-2-(propan-2- 1.82 (m, 2 H); 2.75(m, 2 H); 3.42 (m, 2 535 yloxy)phenyl]amino}-7-(2- H); 3.60 (m, 1 H);3.80 (s, 3 H); 4.57 to 0.83 methoxypyridin-3- 4.68 (m, 2 H); 6.34 (dd, J= 2.1 and 8.4 Hz, yl)thieno[3,2-d]pyrimidine- 1 H); 6.61 (d, J = 2.1 Hz,1 H); 6-carboxamide 7.17 (dd, J = 5.1 and 8.3 Hz, 1 H); 7.45 (broad m, 1H); 7.67 (broad m, 1 H); 7.81 (s, 1 H); 7.87 to 7.93 (m, 2 H); 8.26 (dd,J = 2.0 and 5.1 Hz, 1 H); 9.17 (s, 1 H) I-167 II-5 IIIb-737-(2-Methoxyphenyl)-2- 1.24 (d, J = 6.1 Hz, 6 H); 1.35 (m, 2 H); B({4-[(1-methylpiperidin-4- 1.85 (m, 2 H); 2.02 (m, 2 H); 2.17 (s, 3 547yl)amino]-2-(propan-2- H); 2.71 (m, 2 H); 3.13 (m, 1 H); 3.69 (s, 0.86yloxy)phenyl}amino)thieno[3, 3 H); 4.48 (m, 1 H); 5.09 (broad d,2-d]pyrimidine-6- J = 8.6 Hz, 1 H); 6.00 (dd, J = 2.5 and 8.5 Hz,carboxamide 1 H); 6.28 (d, J = 2.5 Hz, 1 H); 6.82 (broad s, 1 H); 7.08(t, J = 7.8 Hz, 1 H); 7.15 (d, J = 7.8 Hz, 1 H); 7.39 to 7.48 (m, 2 H);7.62 to 7.76 (m, 3 H); 9.09 (s, 1 H) I-168 II-10 IIIb-742-{[1-Cyclobutyl-3-(1- 1.03 (t, J = 7.3 Hz, 3 H); 1.44 to 1.82 (m, Bethylpiperidin-4-yl)-1H- 6 H); 1.94 (m, 2 H); 2.16 (m, 2 H); 550pyrazol-5-yl]amino}-7-(4- 2.34 (q, J = 7.3 Hz, 2 H); 2.42 (m, 3 H); 0.84fluoro-2- 2.91 (m, 2 H); 3.67 (s, 3 H); 4.78 (m, 1 H);methoxyphenyl)thieno[3,2- 6.02 (s, 1 H); 6.88 (td, J = 2.4 and 8.6 Hz,d]pyrimidine-6- 1 H); 6.94 (broad m, 1 H); 7.03 (dd, carboxamide J = 2.4and 11.5 Hz, 1 H); 7.39 (dd, J = 6.8 and 8.6 Hz, 1 H); 7.72 (broad m, 1H); 9.21 (s, 1 H); 9.42 (broad s, 1 H) I-169 II-31 IIIb-667-(2-Methoxypyridin-3-yl)- 1.30 (d, J = 6.1 Hz, 6 H); 2.15 (s, 3 H); B2-({4-[(4-methylpiperazin- 2.55 to 2.45 (broad m, 8 H); 3.38 (s, 2 5481-yl)methyl]-2-(propan-2- H); 3.80 (s, 3 H); 4.63 (m, 1 H); 0.83yloxy)phenyl}amino)thieno[3, 6.68 (dd, J = 1.7 and 8.3 Hz, 1 H); 6.94(d, 2-d]pyrimidine-6- J = 1.7 Hz, 1 H); 7.17 (dd, J = 5.0 and 7.3 Hz,carboxamide 1 H); 7.48 (broad s, 1 H); 7.71 (broad s, 1 H); 7.91 (dd, J= 2.0 and 7.3 Hz, 1 H); 7.96 (s, 1 H); 8.14 (d, J = 8.3 Hz, 1 H); 8.28(dd, J = 2.0 and 5.0 Hz, 1 H); 9.25 (s, 1 H) I-170 II-31 IIIb-717-(2-Methoxypyridin-3-yl)- 1.29 (d, J = 6.1 Hz, 6 H); 1.73 (m, 1 H); B2-{[4-(1-methylpyrrolidin- 2.20 (m, 1 H); 2.30 (s, 3 H); 2.39 (dd, 5193-yl)-2-(propan-2- J = 5.7 and 8.5 Hz, 1 H); 2.61 (m, 2 H); 0.89yloxy)phenyl]amino}thieno[3, 2.83 (t, J = 8.5 Hz, 1 H); 3.27 (partially2-d]pyrimidine-6- masked m, 1 H); 3.80 (s, 3 H); 4.64 (m, carboxamide 1H); 6.66 (dd, J = 2.1 and 8.3 Hz, 1 H); 6.92 (d, J = 2.1 Hz, 1 H); 7.17(dd, J = 5.1 and 7.3 Hz, 1 H); 7.47 (broad m, 1 H); 7.70 (broad m, 1 H);7.91 (dd, J = 2.0 and 7.3 Hz, 1 H); 7.93 (s, 1 H); 8.08 (d, J = 8.3 Hz,1 H); 8.28 (dd, J = 2.0 and 5.1 Hz, 1 H); 9.24 (s, 1 H) I-171 II-5IIIb-75 7-(2-Methoxyphenyl)-2- 1.20 (d, J = 6.1 Hz, 6 H); 2.22 (s, 3 H);B {[3-(4-methylpiperazin-1- 2.47 (partially masked broad m, 4 H); 533yl)-2-(propan-2- 2.99 (broad m, 4 H); 3.70 (s, 3 H); 0.83yloxy)phenyl]amino}thieno[3, 4.85 (m, 1 H); 6.59 (dd, J = 1.5 and 8.3Hz, 1 2-d]pyrimidine-6- H); 6.81 (t, J = 8.3 Hz, 1 H); 7.00 (broadcarboxamide s, 1 H); 7.12 (t, J = 7.8 Hz, 1 H); 7.19 (d, J = 7.8 Hz, 1H); 7.45 to 7.52 (m, 2 H); 7.79 (broad s, 1 H); 7.99 (dd, J = 1.5 and8.3 Hz, 1 H); 8.03 (s, 1 H); 9.25 (s, 1 H) I-172 II-36 IIIb-727-(5-Fluoro-2- 1.23 (d, J = 6.6 Hz, 6 H); 1.54 (m, 2 H); Bmethoxypyridin-3-yl)-2- 1.71 (m, 2 H); 2.70 (m, 1 H); 3.41 (m, 2 512{[1-(propan-2-yl)-3- H); 3.75 (s, 3 H); 3.89 (m, 2 H); 4.50 (m, 1.01(tetrahydro-2H-pyran-4- 1 H); 6.02 (s, 1 H); 7.48 to 7.72 (broadyl)-1H-pyrazol-5- m, 2 H); 7.78 (dd, J = 2.9 and 8.6 Hz, 1yl]amino}thieno[3,2- H); 8.19 (d, J = 2.9 Hz, 1 H); 9.25 (s, 1d]pyrimidine-6- H); 9.43 (broad s, 1 H) carboxamide I-173 II-36 IIIb-647-(5-Fluoro-2- 1.23 (d, J = 6.6 Hz, 6 H); 2.10 (s, 3 H); Bmethoxypyridin-3-yl)-2- 3.76 (s, 3 H); 4.46 (m, 1 H); 5.98 (s, 1 442{[3-methyl-1-(propan-2- H); 7.53 to 7.72 (broad m, 2 H); 0.95yl)-1H-pyrazol-5- 7.82 (dd, J = 3.1 and 8.7 Hz, 1 H); 8.21 (d,yl]amino}thieno[3,2- J = 3.1 Hz, 1 H); 9.23 (s, 1 H); d]pyrimidine-6-9.39 (broad s, 1 H) carboxamide I-174 II-31 IIIb-767-(2-Methoxypyridin-3-yl)- 1.88 (m, 2 H); 2.52 (s, 3 H); 3.00 (m, 2 B2-[(5-methyl-2,3,4,5- H); 3.78 (s, 3 H); 3.87 (m, 2 H); 6.66 (d, 463tetrahydro-1,5- J = 8.6 Hz, 1 H); 7.07 to 7.16 (m, 2 H); 0.90benzoxazepin-7- 7.23 (d, J = 2.1 Hz, 1 H); 7.33 (broad s, 1yl)amino]thieno[3,2- H); 7.67 (broad s, 1 H); 7.82 (dd, J = 2.0d]pyrimidine-6- and 7.3 Hz, 1 H); 8.25 (dd, J = 2.0 and carboxamide 5.1Hz, 1 H); 9.21 (s, 1 H); 9.45 (broad s, 1 H) I-175 II-19 IIIb-722-{[1-(Propan-2-yl)-3- 1.23 (d, J = 6.5 Hz, 6 H); 1.50 (m, 2 H); B(tetrahydro-2H-pyran-4- 1.68 (m, 2 H); 2.68 (m, 1 H); 3.40 (m, 2 547yl)-1H-pyrazol-5- H); 3.89 (m, 2 H); 4.49 (m, 1 H); 5.99 (s, 1.14yl]amino}-7-[2- 1 H); 7.36 (broad m, 1 H); 7.41 to(trifluoromethoxy)phenyl]thieno[3, 7.50 (m, 2 H); 7.57 (m, 2 H); 7.74(broad m, 2-d]pyrimidine-6- 1 H); 9.26 (s, 1 H); 9.41 (broad s, 1 H)carboxamide I-176 II-31 IIIb-75 7-(2-Methoxypyridin-3-yl)- For thisbatch, all the signals are broad B 2-{[3-(4-methylpiperazin- with: 1.20(d, J = 6.0 Hz, 6 H); 2.22 (s, 3 534 1-yl)-2-(propan-2- H); 2.48(partially masked m, 4 H); 0.74 yloxy)phenyl]amino}thieno[3, 2.99 (m, 4H); 3.80 (s, 3 H); 4.83 (m, 1 H); 2-d]pyrimidine-6- 6.60 (d, J = 8.0 Hz,1 H); 6.84 (t, J = 8.2 Hz, carboxamide 1 H); 7.19 (m, 1 H); 7.53 (s, 1H); 7.75 (s, 1 H); 7.90 to 8.00 (m, 2 H); 8.08 (s, 1 H); 8.28 (d, J =5.0 Hz, 1 H); 9.28 (s, 1 H) I-177 II-31 IIIb-687-(2-Methoxypyridin-3-yl)- For this batch, all the signals are broad B2-{[5-(4-methylpiperazin- with: 1.19 (d, J = 6.0 Hz, 6 H); 2.25 (s, 3534 1-yl)-2-(propan-2- H); 2.39 (m, 4 H); 2.71 (m, 4 H); 3.78 (s, 0.82yloxy)phenyl]amino}thieno[3, 3 H); 4.50 (m, 1 H); 6.45 (dd, J = 2.1 and2-d]pyrimidine-6- 8.5 Hz, 1 H); 6.90 (d, J = 8.5 Hz, 1 H); carboxamide7.11 (m, 1 H); 7.41 (s, 1 H); 7.72 (s, 1 H); 7.76 (d, J = 2.1 Hz, 1 H);7.81 (d, J = 7.4 Hz, 1 H); 7.96 (s, 1 H); 8.27 (d, J = 5.0 Hz, 1 H);9.29 (s, 1 H) I-178 II-31 IIIb-73 7-(2-Methoxypyridin-3-yl)- 1.24 (d, J= 6.1 Hz, 6 H); 1.36 (m, 2 H); B 2-({4-[(1-methylpiperidin- 1.85 (m, 2H); 2.01 (m, 2 H); 2.17 (s, 3 548 4-yl)amino]-2-(propan-2- H); 2.70 (m,2 H); 3.13 (m, 1 H); 3.79 (s, 0.73 yloxy)phenyl}amino)thieno[3, 3 H);4.48 (m, 1 H); 5.11 (d, J = 8.3 Hz, 1 2-d]pyrimidine-6- H); 6.03 (dd, J= 2.4 and 8.8 Hz, 1 H); carboxamide 6.29 (d, J = 2.4 Hz, 1 H); 7.11 (dd,J = 5.1 and 7.3 Hz, 1 H); 7.42 (broad s, 1 H); 7.65 (partially maskedbroad s, 1 H); 7.68 (d, J = 8.8 Hz, 1 H); 7.72 (s, 1 H); 7.87 (dd, J =2.0 and 7.3 Hz, 1 H); 8.23 (dd, J = 2.0 and 5.1 Hz, 1 H); 9.12 (s, 1 H)I-179 II-31 IIIb-77 2-{[4-(4-Ethylpiperazin-1- 1.03 (t, J = 7.2 Hz, 3H); 1.26 (d, J = 6.1 Hz, B yl)-2-(propan-2- 6 H); 2.37 (q, J = 7.2 Hz, 2H); 548 yloxy)phenyl]amino}-7-(2- 2.50 (masked m, 4 H); 3.06 (m, 4 H);3.80 (s, 0.79 methoxypyridin-3- 3 H); 4.64 (m, 1 H); 6.34 (dd, J = 2.5and yl)thieno[3,2-d]pyrimidine- 8.8 Hz, 1 H); 6.62 (d, J = 2.5 Hz, 1 H);6-carboxamide 7.17 (dd, J = 4.9 and 7.3 Hz, 1 H); 7.44 (broad s, 1 H);7.67 (broad s, 1 H); 7.83 (s, 1 H); 7.90 (dd, J = 2.0 and 7.3 Hz, 1 H);7.93 (d, J = 8.8 Hz, 1 H); 8.26 (dd, J = 2.0 and 4.9 Hz, 1 H); 9.18 (s,1 H) I-180 II-5 IIIb-78 7-(2-Methoxyphenyl)-2- 1.32 (d, J = 6.0 Hz, 6H); 1.96 (m, 2 H); B {[1-methyl-2-oxo-8- 2.10 (t, J = 6.5 Hz, 2 H); 2.35(broad t, 532 (propan-2-yloxy)-2,3,4,5- J = 6.5 Hz, 2 H); 3.19 (s, 3 H);3.69 (s, 3 1.3 tetrahydro-1H-1- H); 4.71 (m, 1 H); 6.82 (broad m, 1 H);benzazepin-7- 7.00 (s, 1 H); 7.13 (t, J = 7.8 Hz, 1 H);yl]amino}thieno[3,2- 7.20 (d, J = 7.8 Hz, 1 H); 7.41 to 7.55 (m,d]pyrimidine-6- 2 H); 7.76 (broad m, 1 H); 7.91 (s, 1 H); carboxamide8.14 (s, 1 H); 9.25 (s, 1 H) I-181 II-5 IIIb-72 7-(2-Methoxyphenyl)-2-1.23 (d, J = 6.5 Hz, 6 H); 1.52 (m, 2 H); B {[1-(propan-2-yl)-3- 1.68(m, 2 H); 2.68 (m, 1 H); 3.40 (m, 2 493 (tetrahydro-2H-pyran-4- H); 3.67(s, 3 H); 3.90 (m, 2 H); 4.50 (m, 1.03 yl)-1H-pyrazol-5- 1 H); 6.01 (s,1 H); 6.70 (broad m, 1 H); yl]amino}thieno[3,2- 7.07 (t, J = 7.8 Hz, 1H); 7.15 (d, J = 7.8 Hz, d]pyrimidine-6- 1 H); 7.36 (dd, J = 1.8 and 7.8Hz, 1 carboxamide H); 7.45 (td, J = 1.8 and 7.8 Hz, 1 H); 7.75 (broad m,1 H); 9.21 (s, 1 H); 9.37 (broad s, 1 H) I-182 II-31 IIIb-787-(2-Methoxypyridin-3-yl)- 1.32 (d, J = 6.0 Hz, 6 H); 1.99 (m, 2 H); B2-{[1-methyl-2-oxo-8- 2.11 (t, J = 6.5 Hz, 2 H); 2.41 (broad t, 533(propan-2-yloxy)-2,3,4,5- J = 6.5 Hz, 2 H); 3.19 (s, 3 H); 3.79 (s, 31.31 tetrahydro-1H-1- H); 4.71 (m, 1 H); 7.01 (s, 1 H); benzazepin-7-7.15 (dd, J = 5.0 and 7.3 Hz, 1 H); 7.45 (broad yl]amino}thieno[3,2- m,1 H); 7.73 (broad m, 1 H); 7.89 (dd, d]pyrimidine-6- J = 2.0 and 7.3 Hz,1 H); 7.95 (s, 1 H); carboxamide 8.12 (s, 1 H); 8.27 (dd, J = 2.0 and5.0 Hz, 1 H); 9.27 (s, 1 H) I-183 II-31 IIIb-497-(2-Methoxypyridin-3-yl)- 1.33 (d, J = 6.1 Hz, 6 H); 3.81 (s, 3 H); B2-{[4-(1-methyl-1H- 3.85 (s, 3 H); 4.78 (m, 1 H); 6.96 (dd, 516pyrazol-4-yl)-2-(propan-2- J = 2.1 and 8.6 Hz, 1 H); 7.17 to 7.23 (m,1.19 yloxy)phenyl]amino}thieno[3, 2 H); 7.49 (broad m, 1 H); 7.71 (broad2-d]pyrimidine-6- m, 1 H); 7.82 (s, 1 H); 7.94 (dd, J = 2.1 carboxamideand 7.3 Hz, 1 H); 7.98 (s, 1 H); 8.09 (s, 1 H); 8.20 (d, J = 8.6 Hz, 1H); 8.29 (dd, J = 2.1 and 5.0 Hz, 1 H); 9.26 (s, 1 H)

Note 1:

Examples I-1 to I-8 were prepared in hydrochloride form.

Note 2:

Examples I-54, I-55, I-56, I-66, I-67, I-99 and I-139 of Table 4 areobtained after deprotection of the piperidinyl ring, protected on thenitrogen atom with a tert-butyloxycarbonyl group, by treatment with anacid as described in the example below:

7-(2-Methoxyphenyl)-2-{[4-(piperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide

A 1M solution of hydrochloric acid in ethyl acetate (90 ml) is addedslowly to a mixture of 536 mg of 2-methylpropan-2-yl4-[4-{[6-carbamoyl-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-2-yl]amino}-3-(propan-2-yloxy)phenyl]piperidine-1-carboxylatein 5 ml of cold ethyl acetate in an ice bath. After the addition, themixture is stirred at ambient temperature for 18 h, and then theprecipitate is filtered off and rinsed with ether. The solid issuspended in 60 ml of water and 40 ml of a 1M sodium hydroxide solutionare added and the mixture is left to stir for 5 min. The mixture isextracted three times with 100 ml of ethyl acetate. The organic phasesare washed with 50 ml of water and then with 50 ml of a saturated sodiumchloride solution. The organic phases are dried over magnesium sulfate,filtered and concentrated under vacuum. The residue is taken up withether and the solid is filtered off and dried under vacuum, so as toobtain 321 mg of7-(2-methoxyphenyl)-2-{[4-(piperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamidein the form of a yellow solid.

Note 3:

Example I-61 was prepared from Example I-52 according to the followingmethod: 140 mg of 2-methylpropan-2-yl4-[5-{[6-carbamoyl-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-2-yl]amino}-1-(propan-2-yl)-1H-pyrazol-3-yl]piperidine-1-carboxylateare added to a solution of 4 ml of 4N hydrochloric acid in dioxane at atemperature of about 20° C. and the mixture is left to stir for 30minutes. After concentration of the mixture under reduced pressure, asolid is obtained which is washed successively with ethyl ether, withdichloromethane, with dioxane and to finish with dichloromethane. Thesolid is dried under reduced pressure, so as to obtain 112 mg of7-(2-methoxyphenyl)-2-{[3-(piperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}thieno[3,2-d]pyrimidine-6-carboxamidehydrochloride.

Note 4:

Example I-70 was prepared from Example I-61 according to the followingmethod: 57 microlitres of triethylamine and 14 microlitres of iodoethaneare added, at a temperature of about 20° C., to a solution of 69 mg of7-(2-methoxyphenyl)-2-{[3-(piperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}thieno[3,2-d]pyrimidine-6-carboxamidehydrochloride in 1.7 ml of DMF, under an argon atmosphere, and themixture is left to stir for 15 h at ambient temperature. 30 microlitresof triethylamine and 6 microlitres of iodoethane are then added andthen, after stirring for 15 h, a further addition of 30 microlitres oftriethylamine and of 16 microlitres of iodoethane is carried out, whileleaving the mixture to stir for a further 48 hours. The reaction mediumis diluted with 30 ml of ethyl acetate and then the organic phase iswashed three times with 15 ml of water. The aqueous phase is extractedtwice with 25 ml of ethyl acetate. The combined organic phases are driedover magnesium sulfate, filtered and concentrated under vacuum, so as toobtain a yellow solid. The residue is purified by flash chromatographyon silica gel, using a dichloromethane/methanol/NH₄OH (95/5/0.05% to90/10/0.1%) elution gradient, so as to obtain 40 mg of2-{[3-(1-ethylpiperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamidein the form of a yellow solid.

Note 5:

Example I-119 was prepared from 2-methylpropan-2-yl4-[5-({6-carbamoyl-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidin-2-yl}amino)-1-(propan-2-yl)-1H-pyrazol-3-yl]piperidine-1-carboxylate,obtained according to Example 10, according to the following steps:

220 mg of 2-methylpropan-2-yl4-[5-({6-carbamoyl-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidin-2-yl}amino)-1-(propan-2-yl)-1H-pyrazol-3-yl]piperidine-1-carboxylateare added to 5 ml of a 1N solution of hydrochloric acid in ethyl acetateat a temperature of about 20° C. and the mixture is left to stir for 30minutes. A further addition of 3 ml of the 1N acid solution is carriedout and the mixture is left to stir for 15 h. After concentration of themixture under reduced pressure, a solid is obtained which is washedsuccessively with dichloromethane and then with ether. The solid isdried under reduced pressure, so as to obtain 139 mg of2-{[3-(piperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamidehydrochloride.

10 ml of 1N sodium hydroxide are added to a solution of 50 mg of2-{[3-(piperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamidehydrochloride in 10 ml of ethyl acetate. The mixture is stirred, andthen the aqueous phase is extracted twice with 30 ml of ethyl acetate.The combined organic phases are dried over magnesium sulfate, filteredand concentrated under vacuum, so as to obtain 42 mg of2-{[3-(piperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamide.

1 ml of acetic acid, 6 microlitres of 3-oxetanone and 190 mg ofamberlite resin IRA400 cyanoborohydride (Aldrich, loading 2×10⁻³ mol/g)are added, at ambient temperature, to a solution of 50 mg of2-{[3-(piperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamidein 3 ml of anhydrous THF, under an argon atmosphere. After stirring for4 h at ambient temperature, 10 microlitres of 3-oxetanone and 186 mg ofthe same amberlite resin IRA400 cyanoborohydride are added and themixture is left to stir for a further 15 h. A further 6 microlitres of3-oxetanone and 100 mg of amberlite resin IRA400 cyanoborohydride areadded and the mixture is then left to stir for 2 h. The mixture isfiltered and the resin is washed with 50 ml of ethyl acetate then 20 mlof ethanol. The filtrate is concentrated under vacuum and the crudeproduct is purified by flash chromatography on silica gel, elution beingcarried out with a dichloromethane/methanol/NH₄OH (96/4/0.1%) mixture,so as to obtain 30 mg of2-({3-[1-(oxetan-3-yl)piperidin-4-yl]-1-(propan-2-yl)-1H-pyrazol-5-yl}amino)-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamidein the form of a yellow solid.

Note 6:

Example I-123 was prepared from2-{[3-(piperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamidehydrochloride (see note 5), according to the following steps:

70 microlitres of triethylamine and 17 microlitres of iodoethane areadded, at a temperature of about 20° C., to a solution of 100 mg of2-{[3-(piperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamidehydrochloride in 2.5 ml of DMF under an argon atmosphere, and themixture is left to stir for 4 h. 70 microlitres of triethylamine and 10microlitres of iodoethane are then added and then, after stirring for 15h, a further addition of 70 microlitres of triethylamine and 10microlitres of iodoethane is carried out and the mixture is left to stirfor a further 24 hours. The reaction medium is diluted with 40 ml ofethyl acetate and then the organic phase is washed three times with 15ml of water. The aqueous phase is extracted twice with 20 ml of ethylacetate. The combined organic phases are dried over magnesium sulfate,filtered and concentrated under vacuum, so as to obtain a yellow solid.The crude product is purified by flash chromatography on silica gel,elution being carried out with a dichloromethane/methanol/NH₄OH(96/4/0.1%) mixture, so as to obtain 57 mg of2-{[3-(1-ethylpiperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamidein the form of a yellow solid.

Note 7:

Examples I-62 and I-63 are isolated by separation of the enantiomers ofExample I-45 by chiral chromatography according to the followingconditions: Chiralpak IC, 5 μm, 20×250 mm column, detection at λ=254 nm,elution with 60 MTBE/15 heptane/5 methanol/0.1 TEA at a flow rate of 20ml/min. This separation produces I-62 (TR 14.2 min, OR (589 nm) 20.1(c=1.635 mg/0.5 ml DMSO)) and I-63 (TR 19.3 min, OR (589 nm) 20.1(c=1.793 mg/0.5 ml DMSO)).

Note 8:

2-[2-Isopropy-4-(tetrahydropyran-4-ylamino)phenylamino]-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide

Example I-164 was obtained from2-{4-[formyl-(tetrahydropyran-4-yl)amino]-2-isopropoxyphenylamino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide,obtained according to Example 10, according to the following steps:

A mixture of 0.3 g of2-{4-[formyl-(tetrahydropyran-4-yl)amino]-2-isopropoxyphenylamino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamideand 30 ml of a 1.25 M hydrochloric acid solution in methanol is stirredin an autoclave at 60° C. for 15 h. The mixture is concentrated todryness under reduced pressure. The residue is taken up in water andalkalinized with an ammonical solution, and then extracted three timeswith 30 ml of ethyl acetate. The organic phases are combined, dried overmagnesium sulfate and concentrated to dryness under reduced pressure.The residue is purified by chromatography on a 50 g silica column,elution being carried out with a dichloromethane/methanol/acetonitrile(95/5/5 v/v/v) mixture, so as to obtain an impure batch of 0.23 g whichis subjected to a second purification on 50 g of silica, with the sameeluent, so as to obtain 0.20 g of2-[2-isopropy-4-(tetrahydropyran-4-ylamino)phenylamino]-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide.The latter is taken up with stirring in a mixture of 5 ml of diethylether and 5 ml of petroleum ether and then filtered. The yellow solidobtained is dried under vacuum (20 mbar/1 h) at 40° C., so as to obtain0.19 g of2-[2-isopropy-4-(tetrahydropyran-4-ylamino)phenylamino]-7-(2-methoxyphenyl)-thieno[3,2-d]pyrimidine-6-carboxamide,in the form of an orangey-coloured solid (melting point: 192° C.).

Retention time Tr (min)=0.98; [M+H]+: m/z 534 (method B).

Note 9:

2-[2-Isopropoxy-4-(1-methylpiperidin-4-ylamino)phenylamino]-7-(2-methoxy-phenyl)thieno[3,2-d]pyrimidine-6-carboxamide

Example I-167 was obtained from2-{4-[formyl-(1-methylpiperidin-4-yl)amino]-2-isopropoxyphenylamino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide,obtained according to Example 10, according to the following steps:

A 5N hydrochloric acid solution (6.25 ml) is added to a single-neckedround-bottomed flask containing 0.25 g of2-{4-[formyl-(1-methylpiperidin-4-yl)amino]-2-isopropoxyphenylamino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide.The reaction mixture is stirred at ambient temperature for 40 h, andthen a further 2.0 ml of 5N hydrochloric acid solution are added and thestirring is continued for 20 h. The mixture is then poured into 25 ml ofwater and alkalinized by adding a solution of aqueous ammonia at 28% (8ml). After extraction with ethyl acetate (3×30 ml), the organic extractsare combined, washed with water (3×20 ml) to neutral pH, dried overmagnesium sulfate, and then concentrated to dryness under reducedpressure. The residue is purified by chromatography on a 25 g cartridgeof 15-40 μm silica, elution being carried out successively with 94/3/3v/v/v then 90/5/5 v/v/v dichloromethane/methanol/acetonitrile mixtures,and then a dichloromethane/methanol/acetonitrile/28% aqueous ammoniamixture (93/3/3/1 v/v/v/v) at a flow rate of 20 ml/min. The pasty orangesolid obtained is triturated from diisopropyl ether and reconcentratedto dryness under reduced pressure, and then triturated from petroleumether and filtered. The solid obtained is stove-dried under reducedpressure (40° C., 10-3 mbar), so as to obtain 0.13 g of2-[2-isopropoxy-4-(1-methylpiperidin-4-ylamino)phenylamino]-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamidein the form of a dark orange solid.

Retention time Tr (min)=0.86; [M+H]+: m/z 547 (method B).

Note 10:

Example I-93 was obtained from2-{[4-(1-formyl-1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide,obtained according to Example 10, according to the following steps:

A mixture of 76 mg of2-{[4-(1-formyl-1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamideand 2 ml of 5N sodium hydroxide in 15 ml of methanol is stirred atambient temperature for 3 hours, and then maintained at reflux for 1 h30. The mixture is stirred at AT for 15 h and then again maintained atreflux for 5 h 30. The reaction medium is then run into 20 ml of waterand then the methanol is eliminated by concentration under reducedpressure. The resulting aqueous phase is washed several times withdichloromethane (3 times 20 ml) and then acidified so as to obtain a pHwith a value of about 7/8, and then the aqueous phase is extracted afurther three times with 20 ml of dichloromethane. The combined organicphases are dried over magnesium sulfate, filtered and concentrated undervacuum, so as to obtain 72 mg of2-{[4-(1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxylicacid in the form of a brown solid.

A mixture of 40 mg of2-{[4-(1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxylicacid, 63 mg of BOP and 68 mg of HOBt in 20 ml of DMF is stirred atambient temperature for 20 minutes. 23 mg of ammonium chloride and 74 mgof N,N-diisopropylethylamine are then added. The mixture is stirred atAT for 48 h. The residue is purified by flash chromatography on silicagel, using a dichloromethane/methanol (100/0 to 90/10) elution gradient.After concentration of the fractions to dryness, a brown solid isobtained which is repurified by reverse-phase HPLC (Macherey-Nagel250×40 mm, reverse phase C18 Nucleodur 10 μm column; eluent: MeCNcontaining 0.07% TFA, H₂O containing 0.07% TFA; elution gradient from 10to 95% of MeCN; flow rate 70 ml/min and collection by UV detection at254 nm).

The fractions containing the expected product are loaded on to a VarianBond Elut SCX cartridge (2 g) conditioned with methanol. The phase iswashed with methanol and then methanol/NH₃ 7N. After concentration ofthe solvent to dryness, 7 mg of2-{[4-(1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamideare obtained in the form of an orangey-coloured solid.

Example 13:[7-(2-Methoxyphenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol(I-185)

A mixture of 1.80 g of methyl7-(2-methoxyphenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylate,1.37 g ofN-[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]formamide and4.44 g of1-[N-(2-methylpropan-2-yl)-P,P-di(pyrrolidin-1-yl)phosphorimidoyl]pyrrolidine(BTPP) in 50 ml of anhydrous DMF is stirred at ambient temperature for16 h. The mixture is then evaporated under vacuum at a temperature of55° C., and the residue is diluted with ethyl acetate and water. Theaqueous phase is extracted three times with ethyl acetate. The organicphases are washed with a saturated sodium chloride solution, dried overmagnesium sulfate, filtered and concentrated under vacuum. The crudeproduct is purified on 100 g of silica, elution being carried out with0-2.5% of methanol containing 10% by volume of 28% aqueous ammoniasolution in dichloromethane, so as to obtain 2.264 g of methyl2-{formyl[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxylatein the form of a brown solid.

A 1M solution of hydrido[bis(2-methylpropyl)]aluminium in toluene isadded dropwise to a solution of 2.26 g of methyl2-{formyl[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxylatein 30 ml of toluene and 30 ml of THF, cooled to −70° C. under argon.After 5 min, the bath is replaced with a bath of ice-cold water and themixture is stirred for 2 h. The mixture is then cooled to −40° C. andtreated with 10 ml of a saturated ammonium chloride solution, 10 ml ofwater and 30 ml of ethyl acetate. The resulting suspension is filteredon Clarcel and the Clarcel is rinsed with ethyl acetate. The aqueousphase is saturated with sodium chloride and extracted three times withethyl acetate. The organic phases are washed with a saturated sodiumchloride solution, dried over magnesium sulfate, filtered andconcentrated under vacuum, so as to obtain 1.47 g of a mixturecontaining mainly{[6-(hydroxymethyl)-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-2-yl][4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}methanolin the form of an orangey-coloured solid.

A solution of 1.47 g of{[6-(hydroxymethyl)-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-2-yl][4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}methanolmixture in 30 ml of THF and 13.4 ml of 1M sodium hydroxide is stirred atambient temperature for 1 h 40. The mixture is diluted with 80 ml ofethyl acetate and 10 ml of an aqueous 10% citric acid solution. Theaqueous phase is extracted three times with ethyl acetate. The aqueousphase is saturated with sodium chloride and again extracted twice withethyl acetate. The organic phases are washed with a saturated sodiumchloride solution, dried over magnesium sulfate, filtered andconcentrated under vacuum. The crude product is purified on 50 g ofsilica, elution being carried out with 50-100% of acetone indichloromethane, and then with 2-4% of methanol containing 10% by volumeof 28% aqueous ammonia solution in dichloromethane, so as to obtain abrown solid. Trituration from ethyl ether gives 457 mg of[7-(2-methoxyphenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanolin the form of a yellow solid.

Example 14:2-[2-{[2-Methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-6-yl]propan-2-ol(I-210)

A 3M solution of methylmagnesium bromide (11.2 ml) is added slowly to asolution of 2.60 g of methyl7-(2-methoxyphenyl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxylatein 30 ml of THF, cooled to −70° C. The mixture is stirred while allowingthe temperature to come back up to ambient temperature. After 1 h atambient temperature, the mixture is treated with a saturated ammoniumchloride solution and the aqueous phase is extracted with ethyl acetate.The organic phases are dried over sodium sulfate, filtered andconcentrated under vacuum, so as to obtain 2.58 g of2-[7-(2-methoxyphenyl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidin-6-yl]propan-2-olin the form of a yellow powder.

A mixture of 2.58 g of2-[7-(2-methoxyphenyl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidin-6-yl]propan-2-oland 4.08 g of sodium perborate hydrate in 15 ml of acetic acid is heatedat 95° C. for 1 h, and then concentrated under reduced pressure. Theresidue is diluted with 1M sodium hydroxide and extracted with ethylacetate. The organic phases are washed with water, dried over sodiumsulfate, filtered and concentrated under vacuum. The residue is purifiedon 80 g of silica, elution being carried out with dichloromethane, so asto obtain 1.57 g of2-[7-(2-methoxyphenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidin-6-yl]propan-2-olin the form of a yellow powder.

170 mg of sodium hydride at 60% are added to a solution of 424 mg ofN-[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]formamide in 7 ml of DMSO.The mixture is stirred at ambient temperature for 30 min, and then 643mg of2-[7-(2-methoxyphenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidin-6-yl]propan-2-olare added. The mixture is stirred at ambient temperature for 4 h. Themixture is purified on 40 g of silica (solid deposition), elution beingcarried out with 2% methanol in dichloromethane. The fractionscontaining the expected product are combined and concentrated underreduced pressure. The residue is purified by reverse-phase HPLC, elutionbeing carried out with acetonitrile/0.001 M hydrochloric acid, so as toobtain 180 mg of2-[2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-6-yl]propan-2-olhydrochloride in the form of a yellow powder.

Example 15:2-[7-(4-Fluoro-2-methoxyphenyl)-2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]propan-2-ol(I-211)

170 mg of sodium hydride at 60% are added to a solution of 424 mg ofN-[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]formamide in 7 ml of DMSO.The mixture is stirred at ambient temperature for 30 min, and then 674mg of methyl7-(4-fluoro-2-methoxyphenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylateare added. The mixture is stirred at ambient temperature for 4 h. Themixture is purified on silica (solid deposition), elution being carriedout with dichloromethane/cyclohexane (1/1), and then withdichloromethane/methanol/NH₄OH (96/4/0.4). The compound is againpurified on 80 g of silica, elution being carried out withdichloromethane/methanol/NH₄OH (98/2/0.2), so as to obtain 217 mg ofmethyl7-(4-fluoro-2-methoxyphenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxylatein the form of a beige powder.

A 3M solution of methylmagnesium bromide (0.44 ml) is added slowly to asolution of 158 mg of methyl7-(4-fluoro-2-methoxyphenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxylatein 1.2 ml of THF, cooled to 0° C. The mixture is stirred while allowingthe temperature to come back up to ambient temperature. After 1 h atambient temperature, the mixture is treated with a saturated ammoniumchloride solution and the aqueous phase is extracted with ethyl acetate.The organic phases are dried over sodium sulfate, filtered andconcentrated under vacuum. The crude product is purified bychromatography on 40 g of silica, elution being carried out withdichloromethane/methanol (98/2), so as to obtain 150 mg of2-[7-(4-fluoro-2-methoxyphenyl)-2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]propan-2-ol.The solid is treated with one equivalent of a 1M solution ofhydrochloric acid in dioxane and the mixture is concentrated undervacuum, so as to obtain 130 mg of2-[7-(4-fluoro-2-methoxyphenyl)-2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]propan-2-olhydrochloride in the form of an orange powder.

Example 16:[7-(2-Methoxy-6-methylpyridin-3-yl)-2-{[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol(I-191)

0.7 ml of1-[N-(2-methylpropan-2-yl)-P,P-di(pyrrolidin-1-yl)phosphorimidoyl]pyrrolidine(BTPP) is added to a mixture of 300 mg of methyl7-(2-methoxy-6-methylpyridin-3-yl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylateand 231 mg ofN-[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]formamidein 8 ml of anhydrous DMF. The mixture is stirred at ambient temperaturefor 16 h, and then evaporated under vacuum at a temperature of 55° C.,and the residue is diluted with ethyl acetate and water. The aqueousphase is extracted three times with ethyl acetate. The organic phasesare washed with a saturated sodium chloride solution, dried overmagnesium sulfate, filtered and concentrated under vacuum. The crudeproduct is purified on 25 g of silica, elution being carried out with50-100% of acetone in dichloromethane so as to obtain 422 mg of methyl2-{formyl[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxy-6-methylpyridin-3-yl)thieno[3,2-d]pyrimidine-6-carboxylatein the form of an orangey-coloured solid.

4.85 ml of a 1M solution of hydrido[bis(2-methylpropyl)]aluminium intoluene are added dropwise to a solution of 419 mg of methyl2-{formyl[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxy-6-methylpyridin-3-yl)thieno[3,2-d]pyrimidine-6-carboxylatein 15 ml of toluene and 15 ml of THF, cooled to −70° C. under argon.After 5 min, the bath is replaced with a bath of ice-cold water and themixture is stirred for 2 h. The mixture is then cooled to −40° C. andtreated with 30 ml of a saturated ammonium chloride solution and 30 mlof ethyl acetate. The aqueous phase is extracted three times with 15 mlof ethyl acetate. The organic phases are combined with the organicphases of another reaction carried out under the same conditions, butstarting from 145 mg of methyl2-{[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxy-6-methylpyridin-3-yl)thieno[3,2-d]pyrimidine-6-carboxylate.The combined organic phases are washed with a saturated sodium chloridesolution, dried over magnesium sulfate, filtered and concentrated undervacuum, so as to obtain 457 mg of a mixture containing mainly{[6-(hydroxymethyl)-7-(2-methoxy-6-methylpyridin-3-yl)thieno[3,2-d]pyrimidin-2-yl][5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}methanolin the form of a beige solid.

A solution of 457 mg of the{[6-(hydroxymethyl)-7-(2-methoxy-6-methylpyridin-3-yl)thieno[3,2-d]pyrimidin-2-yl][5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}methanolmixture in 30 ml of THF and 4.75 ml of 1 M sodium hydroxide is stirredat ambient temperature for 2 h 15. The mixture is diluted with 80 ml ofethyl acetate, 40 ml of water and 5 ml of an aqueous 10% citric acidsolution. The aqueous phase is extracted three times with 40 ml of ethylacetate. The organic phases are washed with 50 ml of a saturated sodiumchloride solution, dried over magnesium sulfate, filtered andconcentrated under vacuum. The crude product is purified on 25 g ofsilica, elution being carried out with 1-5% of methanol (containing 10%by volume of 28% ammonium hydroxide) in dichloromethane, so as to obtaina brown oil. Placing the oil in solution in 1 ml of acetonitrile andadding diisopropyl ether and pentane gives a suspension which isconcentrated under vacuum. After trituration with pentane, the resultingsolid is filtered off and dried under vacuum, so as to obtain 177 mg of[7-(2-methoxy-6-methylpyridin-3-yl)-2-{[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanolin the form of a beige solid.

Example 17:[7-(5-Fluoro-2-methoxyphenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol(I-202)

0.7 ml of1-[N-(2-methylpropan-2-yl)-P,P-di(pyrrolidin-1-yl)phosphorimidoyl]pyrrolidine(BTPP) is added to a solution of 245 mg ofN-[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]formamide in 5 mlof anhydrous DMF. After 10 min, a solution of 350 mg of methyl7-(5-fluoro-2-methoxyphenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylatein 6.5 ml of anhydrous DMF is added and the mixture is stirred atambient temperature for 42 h. The mixture is then evaporated undervacuum at a temperature of 60° C., and the residue is purified on 120 gof silica, elution being carried out with 5% of methanol indichloromethane, so as to obtain 503 mg of methyl2-{formyl[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(5-fluoro-2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxylatein the form of an orangey-coloured solid.

5.47 ml of a 1M solution of hydrido[bis(2-methylpropyl)]aluminium intoluene are added dropwise to a solution of 500 mg of methyl2-{formyl[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(5-fluoro-2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxylatein 13 ml of anhydrous toluene, cooled to −70° C. under argon. After 3 hat −70° C., 10 ml of a 5N sodium hydroxide solution are added. Afterreturning to ambient temperature, the mixture is extracted three timeswith 10 ml of ethyl acetate. The organic phases are washed with amixture of 10 ml of water and 6 ml of 5N sodium hydroxide. The aqueousphase is extracted twice with 10 ml of ethyl acetate and the combinedorganic phases are dried over magnesium sulfate, filtered andconcentrated under vacuum, so as to obtain 517 mg of a mixturecontaining mainly{[6-(hydroxymethyl)-7-(5-fluoro-2-methoxyphenyl)thieno[3,2-d]pyrimidin-2-yl][4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}methanolin the form of an orangey-coloured solid.

A solution of 517 mg of the{[6-(hydroxymethyl)-7-(5-fluoro-2-methoxyphenyl)thieno[3,2-d]pyrimidin-2-yl][4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}methanolmixture in 24 ml of THF and 10 ml of 1M sodium hydroxide is stirred atambient temperature for 4 h. The mixture is extracted three times with10 ml of ethyl acetate. The organic phases are washed with 10 ml ofwater and the organic phases are concentrated under vacuum. The crudeproduct is purified on 80 g of silica, elution being carried out with5-8% of methanol in dichloromethane, so as to obtain a yellow foam.After trituration with ether, the resulting solid is filtered off anddried under vacuum, so as to obtain 247 mg of[7-(5-fluoro-2-methoxyphenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanolin the form of a yellow solid.

The compounds (I″) obtained according to Examples 13 to 17 are describedin Table 5.

TABLE 5 Compound Compound Compound MS I″ II IIIb Name NMRconditions/MH+/Tr I-184 II-5 IIIb-3 [7-(2-Methoxyphenyl)-2- 1.30 (d, J =6.1 Hz, 6 H); 1.53 to A {[4-(1-methylpiperidin-4- 1.74 (m, m, 4 H); 1.93(m, 2 H); 2.18 (s, 3 519 yl)-2-(propan-2- H); 2.37 (m, 1 H); 2.84 (m, 2H); 0.73 yloxy)phenyl]amino}thieno[3, 3.74 (s, 3 H); 4.66 (m, 3 H); 5.86(t, J = 5.6 Hz, 2-d]pyrimidin-6- 1 H); 6.60 (dd, J = 1.7 and 8.3 Hz,yl]methanol 1 H); 6.86 (d, J = 1.7 Hz, 1 H); 7.10 (t, J = 7.8 Hz, 1 H);7.19 (d, J = 7.8 Hz, 1 H); 7.38 (dd, J = 1.8 and 7.8 Hz, 1 H); 7.47 (dt,J = 1.8 and 7.8 Hz, 1 H); 7.72 (s, 1 H); 8.21 (d, J = 8.3 Hz, 1 H); 9.06(s, 1 H) I-185 II-5 IIIb-25 [7-(2-Methoxyphenyl)-2- 1.27 (d, J = 6.1 Hz,6 H); 2.22 (s, 3 H); B {[4-(4-methylpiperazin- 2.44 (m, 4 H); 3.04 (m, 4H); 3.74 (s, 520 1-yl)-2-(propan-2- 3 H); 4.53 to 4.71 (m, 3 H); 0.79yloxy)phenyl]amino}thieno[3, 5.84 (broad t, J = 5.7 Hz, 1 H); 6.31 (dd,2-d]pyrimidin-6- J = 1.9 and 8.8 Hz, 1 H); 6.61 (d, yl]methanol J = 1.9Hz, 1 H); 7.09 (t, J = 8.0 Hz, 1 H); 7.18 (d, J = 8.0 Hz, 1 H); 7.37(dd, J = 1.7 and 8.0 Hz, 1 H); 7.45 (td, J = 1.7 and 8.0 Hz, 1 H); 7.61(s, 1 H); 8.05 (d, J = 8.8 Hz, 1 H); 9.01 (s, 1 H) I-186 II-47 IIIb-25[7-(2-Methoxy-6- 1.26 (d, J = 6.1 Hz, 6 H); 2.22 (s, 3 H); Bmethylpyridin-3-yl)-2- 2.45 (m, 4 H); 2.50 (masked s, 3 H); 535{[4-(4-methylpiperazin- 3.05 (m, 4 H); 3.83 (s, 3 H); 4.64 (m, 0.791-yl)-2-(propan-2- 3 H); 5.88 (broad s, 1 H); 6.34 (dd,yloxy)phenyl]amino}thieno[3, J = 1.9 and 8.8 Hz, 1 H); 6.61 (d,2-d]pyrimidin-6- J = 1.9 Hz, 1 H); 7.01 (d, J = 7.6 Hz, 1 yl]methanolH); 7.65 (s, 1 H); 7.69 (d, J = 7.6 Hz, 1 H); 7.97 (d, J = 8.8 Hz, 1 H);9.02 (s, 1 H) I-187 II-36 IIIb-25 [7-(5-Fluoro-2- 1.26 (d, J = 6.1 Hz, 6H); 2.22 (s, 3 H); B methoxypyridin-3-yl)-2- 2.45 (m, 4 H); 3.04 (m, 4H); 3.84 (s, 539 {[4-(4-methylpiperazin- 3 H); 4.64 (spt, J = 6.1 Hz, 1H); 0.91 1-yl)-2-(propan-2- 4.69 (d, J = 5.8 Hz, 1 H); 5.94 (t, J = 5.8Hz, yloxy)phenyl]amino}thieno[3, 1 H); 6.31 (dd, J = 2.5 and 9.0 Hz, 12-d]pyrimidin-6- H); 6.62 (d, J = 2.5 Hz, 1 H); 7.72 (s, 1 yl]methanolH); 7.87 (dd, J = 2.9 and 8.8 Hz, 1 H); 7.95 (d, J = 9.0 Hz, 1 H); 8.28(d, J = 2.9 Hz, 1 H); 9.04 (s, 1 H) I-188 II-44 IIIb-25[7-(2-Ethoxypyridin-3- 1.21 (t, J = 7.2 Hz, 3 H); 1.27 (d, J = 6.1 Hz, Byl)-2-{[4-(4- 6 H); 2.22 (s, 3 H); 2.44 (m, 4 H); 535methylpiperazin-1-yl)-2- 3.04 (m, 4 H); 4.34 (q, J = 7.2 Hz, 2 0.91(propan-2- H); 4.65 (spt, J = 6.1 Hz, 1 H); yloxy)phenyl]amino}thieno[3,4.69 (broad s, 2 H); 5.92 (broad s, 1 H); 2-d]pyrimidin-6- 6.32 (dd, J =2.6 and 8.9 Hz, 1 H); yl]methanol 6.62 (d, J = 2.6 Hz, 1 H); 7.15 (dd, J= 5.0 and 7.3 Hz, 1 H); 7.66 (s, 1 H); 7.83 (dd, J = 2.0 and 7.3 Hz, 1H); 8.00 (d, J = 8.9 Hz, 1 H); 8.26 (dd, J = 2.0 and 5.0 Hz, 1 H); 9.03(s, 1 H) I-189 II-31 IIIb-26 [7-(2-Methoxypyridin-3- 1.28 (d, J = 6.1Hz, 6 H); 2.03 (s, 3 H); B yl)-2-{[5-methyl-4-(4- 2.22 (s, 3 H); 2.45(broad m, 4 H); 535 methylpiperazin-1-yl)-2- 2.77 (m, 4 H); 3.85 (s, 3H); 4.59 (m, 0.89 (propan-2- 1 H); 4.67 (d, J = 5.7 Hz, 2 H); 5.92 (t,yloxy)phenyl]amino}thieno[3, J = 5.7 Hz, 1 H); 6.68 (s, 1 H);2-d]pyrimidin-6- 7.17 (dd, J = 4.9 and 7.3 Hz, 1 H); 7.68 (s,yl]methanol 1 H); 7.85 (dd, J = 2.1 and 7.3 Hz, 1 H); 8.07 (s, 1 H);8.29 (dd, J = 2.1 and 4.9 Hz, 1 H); 9.07 (s, 1 H) I-190 II-36 IIIb-26[7-(5-Fluoro-2- 1.28 (d, J = 6.1 Hz, 6 H); 2.04 (s, 3 H); Bmethoxypyridin-3-yl)-2- 2.23 (s, 3 H); 2.45 (broad m, 4 H); 553{[5-methyl-4-(4- 2.77 (m, 4 H); 3.84 (s, 3 H); 4.59 (m, 0.95methylpiperazin-1-yl)-2- 1 H); 4.70 (d, J = 5.7 Hz, 2 H); 5.95 (t,(propan-2- J = 5.7 Hz, 1 H); 6.69 (s, 1 H); 7.73 (s,yloxy)phenyl]amino}thieno[3, 1 H); 7.89 (dd, J = 2.9 and 8.7 Hz, 12-d]pyrimidin-6- H); 8.04 (s, 1 H); 8.29 (d, J = 2.9 Hz, 1 yl]methanolH); 9.08 (s, 1 H) I-191 II-47 IIIb-26 [7-(2-Methoxy-6- 1.28 (d, J = 6.1Hz, 6 H); 2.04 (s, 3 H); B methylpyridin-3-yl)-2- 2.23 (s, 3 H); 2.45(m, 4 H); 549 {[5-methyl-4-(4- 2.50 (masked s, 3 H); 2.78 (m, 4 H); 0.84methylpiperazin-1-yl)-2- 3.82 (s, 3 H); 4.59 (m, 1 H); 4.67 (d, J = 5.7Hz, (propan-2- 2 H); 5.90 (t, J = 5.7 Hz, 1 H);yloxy)phenyl]amino}thieno[3, 6.69 (s, 1 H); 7.01 (d, J = 7.6 Hz, 1 H);2-d]pyrimidin-6- 7.67 (s, 1 H); 7.71 (d, J = 7.6 Hz, 1 H); yl]methanol8.09 (s, 1 H); 9.05 (s, 1 H) I-192 II-47 IIIb-72 [7-(2-Methoxy-6- 1.25(d, J = 6.1 Hz, 6 H); 1.53 (m, 2 B methylpyridin-3-yl)-2- H); 1.69 (m, 2H); 2.47 (s, 3 H); 495 {[1-(propan-2-yl)-3- 2.69 (m, 1 H); 3.41 (m, 2H); 3.80 (s, 3 H); 1.11 (tetrahydro-2H-pyran-4- 3.90 (m, 2 H); 4.55 (m,1 H); 4.64 (d, yl)-1H-pyrazol-5- J = 5.6 Hz, 2 H); 5.89 (t, J = 5.6 Hz,1 yl]amino}thieno[3,2- H); 6.06 (s, 1 H); 6.96 (d, J = 7.6 Hz, 1d]pyrimidin-6- H); 7.63 (d, J = 7.6 Hz, 1 H); 9.07 (s, 1 yl]methanol H);9.27 (s, 1 H) I-193 II-44 IIIb 26 [7-(2-Ethoxypyridin-3- 1.18 (t, J =7.2 Hz, 2 H); 1.28 (d, J = 6.1 Hz, B yl)-2-{[5-methyl-4-(4- 4 H); 2.03(s, 3 H); 2.23 (s, 3 H); 549 methylpiperazin-1-yl)-2- 2.45 (broad m, 4H); 2.77 (m, 4 H); 0.98 (propan-2- 4.34 (q, J = 7.2 Hz, 2 H); 4.59 (m, 1yloxy)phenyl]amino}thieno[3, H); 4.69 (broad m, 1 H); 5.93 (broad2-d]pyrimidin-6- t, J = 5.6 Hz, 1 H); 6.69 (s, 1 H); yl]methanol 7.15(dd, J = 5.0 and 7.5 Hz, 1 H); 7.68 (s, 1 H); 7.85 (dd, J = 2.1 and 7.5Hz, 1 H); 8.07 (s, 1 H); 8.27 (dd, J = 2.1 and 5.0 Hz, 1 H); 9.07 (s, 1H) I-194 II-5 IIIb-26 [7-(2-Methoxyphenyl)-2- 1.28 (d, J = 6.1 Hz, 6 H);2.01 (s, 3 H); B {[5-methyl-4-(4- 2.22 (s, 3 H); 2.44 (m, 4 H); 2.76 (m,534 methylpiperazin-1-yl)-2- 4 H); 3.73 (s, 3 H); 4.54 to 4.69 (m, 30.85 (propan-2- H); 5.85 (t, J = 5.7 Hz, 1 H); 6.68 (s, 1yloxy)phenyl]amino}thieno[3, H); 7.10 (t, J = 7.8 Hz, 1 H); 7.18 (d,2-d]pyrimidin-6- J = 7.8 Hz, 1 H); 7.39 (dd, J = 1.7 and yl]methanol 7.8Hz, 1 H); 7.45 (dt, J = 1.7 and 7.8 Hz, 1 H); 7.64 (s, 1 H); 8.12 (s, 1H); 9.04 (s, 1 H) I-195 II-47 IIIb-80 [7-(2-Methoxy-6- 1.25 (d, J = 6.1Hz, 6 H); 1.65 (m, 1 B methylpyridin-3-yl)-2- H); 1.69 to 1.81 (m, 4 H);2.08 (m, 1 575 {[4-(1-methyl-1,7- H); 2.24 (s, 3 H); 2.50 (masked s, 31.01 diazaspiro[4.4]non-7- H); 2.64 (m, 1 H); 2.74 (m, 1 H);yl)-2-(propan-2- 2.91 (d, J = 9.5 Hz, 1 H); 3.19 (m, 1 H);yloxy)phenyl]amino}thieno[3, 3.26 (partially masked d, J = 9.5 Hz, 12-d]pyrimidin-6- H); 3.33 (m, 1 H); 3.83 (s, 3 H); 4.57 yl]methanol to4.65 (m, 3 H); 5.86 (t, J = 5.8 Hz, 1 H); 5.97 (dd, J = 2.2 and 8.6 Hz,1 H); 6.19 (d, J = 2.2 Hz, 1 H); 7.00 (d, J = 7.5 Hz, 1 H); 7.58 (s, 1H); 7.68 (d, J = 7.5 Hz, 1 H); 7.83 (d, J = 8.6 Hz, 1 H); 8.97 (s, 1 H)I-196 II-31 IIIb-79 [2-{[4-Chloro-2-(propan- 1.30 (d, J = 6.1 Hz, 6 H);3.85 (s, 3 H); B 2-yloxy)phenyl]amino}- 4.66 to 4.77 (m, 3 H); 5.95(broad s, 457 7-(2-methoxypyridin-3- 1 H); 6.78 (dd, J = 2.2 and 8.8 Hz,1 1.59 yl)thieno[3,2- H); 7.09 (d, J = 2.2 Hz, 1 H); 7.19 (dd,d]pyrimidin-6- J = 5.1 and 7.4 Hz, 1 H); 7.85 (dd, yl]methanol J = 1.7and 7.4 Hz, 1 H); 7.88 (s, 1 H); 8.27 (d, J = 8.8 Hz, 1 H); 8.30 (dd, J= 1.7 and 5.1 Hz, 1 H); 9.14 (s, 1 H) I-197 II-19 IIIb-64(2-{[3-Methyl-1-(propan- 1.22 (d, J = 6.6 Hz, 6 H); 2.07 (s, 3 H); B2-yl)-1H-pyrazol-5- 4.41 (spt, J = 6.6 Hz, 1 H); 4.63 (broad 464yl]amino}-7-[2- m, 2 H); 5.89 (s, 1 H); 5.98 (broad t, 1.22(trifluoromethoxy)phenyl]thieno[3, J = 5.6 Hz, 1 H); 7.46 to 7.62 (m, 4H); 2-d]pyrimidin- 9.06 (s, 1 H); 9.12 (broad s, 1 H) 6-yl)methanolI-198 II-36 IIIb-64 [7-(5-Fluoro-2- 1.23 (d, J = 6.6 Hz, 6 H); 2.08 (s,3 H); B methoxypyridin-3-yl)-2- 3.81 (s, 3 H); 4.44 (spt, J = 6.6 Hz, 1429 {[3-methyl-1-(propan-2- H); 4.66 (d, J = 5.4 Hz, 2 H); 5.94 (m, 1.05yl)-1H-pyrazol-5- 2 H); 7.80 (dd, J = 2.9 and 8.6 Hz, 1yl]amino}thieno[3,2- H); 8.24 (d, J = 2.9 Hz, 1 H); 9.07 (s, 1d]pyrimidin-6- H); 9.19 (broad s, 1 H) yl]methanol I-199 II-19 IIIb-72(2-{[1-(Propan-2-yl)-3- 1.23 (broad m, 6 H); 1.50 (m, 2 H); B(tetrahydro-2H-pyran-4- 1.69 (m, 2 H); 2.68 (m, 1 H); 3.39 (m, 534yl)-1H-pyrazol-5- 2 H); 3.88 (m, 2 H); 4.48 (spt, J = 6.6 Hz, 1.27yl]amino}-7-[2- 1 H); 4.64 (broad m, 2 H);(trifluoromethoxy)phenyl]thieno[3, 5.98 (broad s, 1 H); 6.01 (s, 1 H);7.45 to 2-d]pyrimidin- 7.63 (m, 4 H); 9.09 (s, 1 H); 6-yl)methanol 9.22(broad s, 1 H) I-200 II-5 IIIb-72 [7-(2-Methoxyphenyl)-2- 1.23 (d, J =6.6 Hz, 6 H); 1.52 (m, 2 B {[1-(propan-2-yl)-3- H); 1.69 (m, 2 H); 2.69(m, 1 H); 480 (tetrahydro-2H-pyran-4- 3.40 (m, 2 H); 3.69 (s, 3 H); 3.89(d, 1.2 yl)-1H-pyrazol-5- J = 14.0 Hz, 2 H); 4.49 (dt, J = 6.6 andyl]amino}thieno[3,2- 13.0 Hz, 1 H); 4.60 (broad m, 2 H); d]pyrimidin-6-5.85 (broad t, J = 5.7 Hz, 1 H); 6.03 (s, yl]methanol 1 H); 7.04 (t, J =7.8 Hz, 1 H); 7.12 (d, J = 7.8 Hz, 1 H); 7.29 (dd, J = 1.8 and 7.5 Hz, 1H); 7.40 (m, 1 H); 9.05 (s, 1 H); 9.17 (s, 1 H) I-201 II-11 IIIb-64[7-(5-Fluoro-2- 1.23 (d, J = 6.5 Hz, 6 H); 2.08 (s, 3 H); Bmethoxyphenyl)-2-{[3- 3.69 (s, 3 H); 4.45 (spt, J = 6.5 Hz, 1 428methyl-1-(propan-2-yl)- H); 4.61 (broad s, 2 H); 5.88 (broad 1.041H-pyrazol-5- s, 1 H); 5.95 (s, 1 H); 7.12 (dd, J = 4.6yl]amino}thieno[3,2- and 9.0 Hz, 1 H); 7.17 (dd, J = 3.2 andd]pyrimidin-6- 9.0 Hz, 1 H); 7.24 (dt, J = 3.2 and 9.0 Hz, yl]methanol 1H); 9.04 (s, 1 H); 9.14 (s, 1 H) I-202 II-11 IIIb-25 [7-(5-Fluoro-2-1.27 (d, J = 6.1 Hz, 6 H); 2.22 (s, 3 H); B methoxyphenyl)-2-{[4- 2.44(m, 4 H); 3.04 (m, 4 H); 3.72 (s, 538 (4-methylpiperazin-1- 3 H); 4.64(m, 3 H); 5.87 (t, J = 5.7 Hz, 0.82 yl)-2-(propan-2- 1 H); 6.31 (dd, J =2.6 and 8.9 Hz, 1 yloxy)phenyl]amino}thieno[3, H); 6.62 (d, J = 2.6 Hz,1 H); 7.17 (dd, 2-d]pyrimidin-6- J = 4.6 and 9.0 Hz, 1 H); 7.23 toyl]methanol 7.33 (m, 2 H); 7.66 (broad s, 1 H); 8.02 (d, J = 8.9 Hz, 1H); 9.02 (s, 1 H) I-203 II-19 IIIb-25 (2-{[4-(4- 1.25 (d, J = 6.1 Hz, 6H); 2.22 (s, 3 H); B Methylpiperazin-1-yl)-2- 2.44 (m, 4 H); 3.04 (m, 4H); 4.56 to 574 (propan-2- 4.76 (m, 3 H); 5.97 (t, J = 5.7 Hz, 1 H);0.89 yloxy)phenyl]amino}-7- 6.30 (dd, J = 2.5 and 8.8 Hz, 1 H); [2- 6.60(d, J = 2.5 Hz, 1 H); 7.49 to (trifluoromethoxy)phenyl]thieno[3, 7.65(m, 4 H); 7.66 (s, 1 H); 7.94 (d, J = 8.8 Hz, 2-d]pyrimidin- 1 H); 9.05(s, 1 H) 6-yl)methanol I-204 II-31 IIIb-49 [7-(2-Methoxypyridin-3- 1.33(d, J = 6.1 Hz, 6 H); 3.85 (s, 3 H); B yl)-2-{[4-(1-methyl-1H- 3.87 (s,3 H); 4.69 (broad d, J = 5.3 Hz, 503 pyrazol-4-yl)-2-(propan- 2 H); 4.78(spt, J = 6.1 Hz, 1 H); 1.28 2- 5.94 (broad t, J = 5.3 Hz, 1 H);yloxy)phenyl]amino}thieno[3, 6.94 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.18 to2-d]pyrimidin-6- 7.23 (m, 2 H); 7.80 (s, 1 H); 7.83 (s, 1 yl]methanolH); 7.87 (dd, J = 2.0 and 7.3 Hz, 1 H); 8.08 (s, 1 H); 8.24 (d, J = 8.3Hz, 1 H); 8.32 (dd, J = 2.0 and 4.9 Hz, 1 H); 9.11 (s, 1 H) I-205 II-5IIIb-49 [7-(2-Methoxyphenyl)-2- 1.33 (d, J = 6.1 Hz, 6 H); 3.75 (s, 3H); B {[4-(1-methyl-1H- 3.85 (s, 3 H); 4.66 (broad m, 2 H); 502pyrazol-4-yl)-2-(propan- 4.77 (spt, J = 6.1 Hz, 1 H); 5.87 (broad 1.342- t, J = 5.7 Hz, 1 H); 6.93 (d, J = 7.8 Hz, 1yloxy)phenyl]amino}thieno[3, H); 7.12 (t, J = 7.8 Hz, 1 H); 7.17 to2-d]pyrimidin-6- 7.24 (m, 2 H); 7.40 (d, J = 7.8 Hz, 1 yl]methanol H);7.48 (t, J = 7.8 Hz, 1 H); 7.79 (s, 1 H); 7.80 (s, 1 H); 8.07 (s, 1 H);8.30 (d, J = 8.6 Hz, 1 H); 9.09 (s, 1 H) I-206 II-49 IIIb-26[2-{[5-Methyl-4-(4- 1.29 (d, J = 6.1 Hz, 6 H); 2.11 (s, 3 H); Bmethylpiperazin-1-yl)-2- 2.25 to 2.93 (partially masked broad 519(propan-2- m, 8 H); 2.56 (s, 3 H); 4.61 (spt, 0.59yloxy)phenyl]amino}-7- J = 6.1 Hz, 1 H); 4.87 (d, J = 5.6 Hz, 2(6-methylpyridin-3- H); 6.00 (t, J = 5.6 Hz, 1 H); 6.71 (s, 1yl)thieno[3,2- H); 7.42 (d, J = 8.1 Hz, 1 H); 7.75 (s, 1 d]pyrimidin-6-H); 7.94 (dd, J = 2.4 and 8.1 Hz, 1 H); yl]methanol 8.17 (s, 1 H); 8.70(d, J = 2.4 Hz, 1 H); 9.11 (s, 1 H) I-207 II-31 IIIb-25[7-(2-Methoxypyridin-3- 1.27 (d, J = 6.1 Hz, 6 H); 2.22 (s, 3 H); Byl)-2-{[4-(4- 2.44 (m, 4 H); 3.05 (m, 4 H); 3.85 (s, 521methylpiperazin-1-yl)-2- 3 H); 4.57 to 4.72 (m, 3 H); 5.89 (t, 0.72(propan-2- J = 5.7 Hz, 1 H); 6.31 (dd, J = 2.6 andyloxy)phenyl]amino}thieno[3, 8.8 Hz, 1 H); 6.61 (d, J = 2.6 Hz, 1 H);2-d]pyrimidin-6- 7.17 (dd, J = 5.0 and 7.4 Hz, 1 H); yl]methanol 7.66(s, 1 H); 7.83 (dd, J = 2.0 and 7.4 Hz, 1 H); 7.98 (d, J = 8.8 Hz, 1 H);8.29 (dd, J = 2.0 and 5.0 Hz, 1 H); 9.03 (s, 1 H) I-208 II-5 IIIb-71[7-(2-Methoxyphenyl)-2- 1.30 (d, J = 6.1 Hz, 6 H); 1.72 (m, 1 B{[4-(1-methylpyrrolidin- H); 2.19 (m, 1 H); 2.29 (s, 3 H); 5053-yl)-2-(propan-2- 2.37 (t, J = 8.6 Hz, 1 H); 2.60 (m, 2 H); 0.81yloxy)phenyl]amino}thieno[3, 2.82 (t, J = 8.6 Hz, 1 H); 3.23 (partially2-d]pyrimidin-6- masked m, 1 H); 3.74 (s, 3 H); 4.56 yl]methanol to 4.72(m, 3 H); 5.85 (broad t, J = 5.7 Hz, 1 H); 6.63 (broad d, J = 8.3 Hz, 1H); 6.90 (broad s, 1 H); 7.10 (t, J = 7.8 Hz, 1 H); 7.18 (d, J = 7.8 Hz,1 H); 7.38 (d, J = 7.8 Hz, 1 H); 7.47 (t, J = 7.8 Hz, 1 H); 7.73 (s, 1H); 8.19 (d, J = 8.3 Hz, 1 H); 9.07 (s, 1 H) I-209 II-1 IIIb-242-(2-{[2-Methoxy-4-(4- 1.36 (s, 6 H); 2.81 (d, J = 4.8 Hz, 3 H); Emethylpiperazin-1- 3.02 (m, 2 H); 3.13 (m, 2 H); 490 yl)phenyl]amino}-7-3.45 (partially masked m, 2 H); 3.72 (m, 2 0.75 phenylthieno[3,2- H);3.81 (s, 3 H); 6.29 (dd, J = 2.5 and d]pyrimidin-6-yl)propan- 8.8 Hz, 1H); 6.66 (d, J = 2.5 Hz, 1 H); 2-ol 7.31 (m, 2 H); 7.43 to 7.54 (m, 3H); 7.78 (d, J = 8.8 Hz, 1 H); 7.84 (broad m, 1 H); 9.01 (s, 1 H); 10.72(broad m, 1 H) I-210 II-5 IIIb-24 2-[2-{[2-Methoxy-4-(4- 1.25 (s, 3 H);1.37 (s, 3 H); E methylpiperazin-1- 2.72 (broad s, 3 H); 3.00 to 3.50(partially 520 yl)phenyl]amino}-7-(2- masked broad m, 8 H); 3.65 (s, 3H); 0.82 methoxyphenyl)thieno[3, 3.80 (s, 3 H); 6.28 (dd, J = 2.5 and8.8 Hz, 2-d]pyrimidin-6- 1 H); 6.64 (d, J = 2.5 Hz, 1 H); yl]propan-2-ol7.04 (td, J = 1.3 and 7.5 Hz, 1 H); 7.10 to 7.16 (m, 2 H); 7.25 (broadm, 1 H); 7.45 (ddd, J = 2.0 and 7.5 and 8.3 Hz, 1 H); 7.78 (d, J = 8.8Hz, 1 H); 8.95 (s, 1 H); 10.64 (broad m, 1 H) I-211 II-10 IIIb-242-[7-(4-Fluoro-2- Spectrum at 500 MHz: 1.25 (s, 3 H); Emethoxyphenyl)-2-{[2- 1.37 (s, 3 H); 2.82 (d, J = 4.7 Hz, 3 H); 538methoxy-4-(4- 3.00 (m, 2 H); 3.15 (m, 2 H); 3.48 (m, 0.85methylpiperazin-1- 2 H); 3.67 (s, 3 H); 3.74 (m, 2 H);yl)phenyl]amino}thieno[3, 3.81 (s, 3 H); 6.34 (dd, J = 2.5 and 8.8 Hz,2-d]pyrimidin-6- 1 H); 6.67 (d, J = 2.5 Hz, 1 H); yl]propan-2-ol 6.88(dt, J = 2.5 and 8.5 Hz, 1 H); 7.07 (dd, J = 2.5 and 11.5 Hz, 1 H); 7.16(dd, J = 7.0 and 8.5 Hz, 1 H); 7.75 (d, J = 8.8 Hz, 1 H); 7.87 (broad m,1 H); 8.97 (s, 1 H); 10.47 (broad m, 1 H)

The compounds according to the invention were the subject ofpharmacological tests for determining their ALK kinase-inhibitingeffect.

Tests consisted in measuring the in vitro activity of the compounds ofthe invention on ALK.

A first test uses a GST-Alk protein (wild-type form 1058-1620), obtainedfrom Carna Biosciences (reference 08-518).

The reagents used have the following composition:

-   -   Enzyme buffer (EB): 50 mM HEPES (pH: 7.0) (Sigma H7523), 100 mM        NaCl (Sigma S7653), NaN₃ at 0.01% (Sigma S8032), BSA at 0.005%        (Sigma A2153). 0.05 mM sodium orthovanadate (Calbiochem 567540).    -   Detection buffer (DB): 50 mM HEPES (pH: 7.0), BSA at 0.1%, 0.8 M        KF (Fluka 60239), 20 mM EDTA (Sigma E5134).

The peptide used is the one described in Biochemistry, 2005, 44,8533-8542; A-21-K(biotin)NH₂, obtained from NeoMPS (reference SP081233).All the HTRF reagents Mab PT66-K (61T66KLB) and streptavidin-XL665(610SAXLB), and the SEB reagent, are purchased from Cisbio.

The test is carried out in a 384-well plate (Greiner 784076). The serialdilutions are carried out in pure DMSO, and then an intermediateone-in-three dilution in water is carried out, with 1 microlitre of eachconcentration being distributed, all these operations being performedusing the Zephyr apparatus (Caliper Life Sciences). The substrate/ATPmixture is prepared in the following way: addition of ATP (finalconcentration 400 microM, Sigma A7699), of the peptide (finalconcentration 1 microM) and of the SEB reagent (final concentration 1.56nM) to the EB, which is then distributed as 7 μl. The enzymatic reactionis initiated by adding 2 μl of enzymatic mixture (final concentration 2nM) in EB supplemented with DTT (final concentration 1 mM, Sigma D5545).These two distributions are carried out with a multichannel pipette(biohit). The plate is incubated at 30° C. for 1 hour. In order to stopthe enzymatic reaction, 10 microlitres of the detection mixture,prepared by adding the two antibodies, Mab PT66-K andstreptavidin-XL665, to the DB, are added. The incubation time beforereading is overnight at 4° C. The HTRF signal is detected on a Rubystarapparatus (BMG Labtech).

A second test uses a commercial GST-Alk protein (mutant L1196M1058-1620) from Carnabio Sciences (08-529). The protocol is the same asthe one for the wild-type form, but the final ATP concentration is 200microM and the final enzyme concentration is 1 nM.

The inhibitory activity with respect to ALK in these tests is given bythe concentration which inhibits 50% of the ALK activity (or IC₅₀).

The IC₅₀ values for the compounds according to the invention are lessthan 1 μM, preferably less than 10 μM, and more particularly less than100 nM.

The table hereinafter indicates the activity results for compoundsaccording to the invention.

ALK L1196M Ex. No. Name ALK (nM) (nM) I-7 2-({2-Methoxy-4-[4-(propan-2-28 NT yl)piperazin-1-yl]phenyl}amino)-7-phenylthieno[3,2-d]pyrimidine-6- carboxamide I-132-{[2-Methoxy-5-methyl-4-(1- 14 NT methylpiperidin-4-yl)phenyl]amino}-7-phenylthieno[3,2-d]pyrimidine-6- carboxamide I-167-(2-Methoxyphenyl)-2-{[4-(1- 7 NT methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2- d]pyrimidine-6-carboxamide I-262-{[4-(1-Methylpiperidin-4-yl)-2- 0.5 NT(propan-2-yloxy)phenyl]amino}-7-[2- (trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamide I-38 7-(2-Methoxyphenyl)-2-{[6-(1- 7 NTmethylpiperidin-4-yl)-4-(propan-2- yloxy)pyridin-3-yl]amino}thieno[3,2-d]pyrimidine-6-carboxamide I-100 7-(2-Methoxypyridin-3-yl)-2-{[5- 3 3methyl-4-(4-methylpiperazin-1-yl)-2- (propan-2-yloxy)phenyl]amino}thieno[3,2- d]pyrimidine-6-carboxamide I-1157-(2-Methylfuran-3-yl)-2-{[4-(1- 13 17methylpiperidin-4-yl)-2-(propan-2- yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide I-118 2-({4-[3-(Dimethylamino)pyrrolidin-1- 22 yl]-5-methyl-2-(propan-2- yloxy)phenyl}amino)-7-(2-methoxyphenyl)thieno[3,2- d]pyrimidine-6-carboxamide I-1232-{[3-(1-Ethylpiperidin-4-yl)-1- 0.5 4(propan-2-yl)-1H-pyrazol-5-yl]amino}- 7-[2-(trifluoromethoxy)phenyl]-thieno[3,2-d]pyrimidine-6- carboxamide I-1277-(2-Methoxyphenyl)-2-{[4-(1-methyl- 43 54 1H-pyrazol-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2- d]pyrimidine-6-carboxamide I-1312-{[5-Fluoro-4-(1-methylpiperidin-4- 3 1yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxypyridin-3-yl)thieno[3,2- d]pyrimidine-6-carboxamide I-1327-(2-Methoxypyridin-3-yl)-2-{[5- 17 65methyl-4-(2-methyl-1H-imidazol-1-yl)- 2-(propan-2-yloxy)phenyl]amino}thieno[3,2- d]pyrimidine-6-carboxamide I-1597-(2-Methoxyphenyl)-2-({4-[(4- 4 9 methylpiperazin-1-yl)methyl]-2-(propan-2- yloxy)phenyl}amino)thieno[3,2- d]pyrimidine-6-carboxamideI-164 7-(2-Methoxyphenyl)-2-{[2-(propan-2- 35 57yloxy)-4-(tetrahydro-2H-pyran-4- ylamino)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide I-172 7-(5-Fluoro-2-methoxypyridin-3-yl)-2- 813 {[1-(propan-2-yl)-3-(tetrahydro-2H- pyran-4-yl)-1H-pyrazol-5-yl]amino}thieno[3,2-d]pyrimidine-6- carboxamide I-1767-(2-Methoxypyridin-3-yl)-2-{[3-(4- 23 43methylpiperazin-1-yl)-2-(propan-2- yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide I-180 7-(2-Methoxyphenyl)-2-{[1-methyl-2- 310424 oxo-8-(propan-2-yloxy)-2,3,4,5- tetrahydro-1H-1-benzazepin-7-yl]amino}thieno[3,2-d]pyrimidine-6- carboxamide I-191[7-(2-Methoxy-6-methylpyridin-3-yl)-2- 12 14{[5-methyl-4-(4-methylpiperazin-1-yl)- 2-(propan-2-yloxy)phenyl]amino}thieno[3,2- d]pyrimidin-6-yl]methanol I-202[7-(5-Fluoro-2-methoxyphenyl)-2-{[4- 27 29(4-methylpiperazin-1-yl)-2-(propan-2- yloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl]methanol I-210 2-[2-{[2-Methoxy-4-(4- 130 NTmethylpiperazin-1-yl)phenyl]amino}-7- (2-methoxyphenyl)thieno[3,2-d]pyrimidin-6-yl]propan-2-ol NT: not tested

It therefore appears that the compounds according to the invention havean ALK-inhibiting activity.

The compounds according to the invention can therefore be used forpreparing medicaments, in particular ALK-inhibiting medicines.

Thus, according to another of its aspects, a subject of the invention ismedicaments which comprise a compound of formula (I), (I′) or (I″), oran addition salt thereof with a pharmaceutically acceptable acid.

The present invention also relates to a medicament comprising a compoundof formula (I), (I′) or (I″) as defined above, or a pharmaceuticallyacceptable salt thereof.

These medicaments are of use in therapy, in particular in the treatmentof cancer.

Among these cancers, attention is given to the treatment of solid orliquid tumours, and to the treatment of cancers which are resistant tocytotoxic agents.

According to another of its aspects, the present invention relates topharmaceutical compositions comprising, as active ingredient, a compoundaccording to the invention. These pharmaceutical compositions contain aneffective dose of at least one compound according to the invention, or apharmaceutically acceptable salt, and also at least one pharmaceuticallyacceptable excipient.

Said excipients are selected, according to the pharmaceutical form andthe mode of administration desired, from the usual excipients which areknown to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration, theactive ingredient of formula (I), (I′) or (I″) above, or the saltthereof, can be administered in unit administration form, as a mixturewith conventional pharmaceutical excipients, to animals and to humanbeings for the treatment of the disorders and diseases above.

The suitable unit administration forms include oral forms such astablets, soft or hard gel capsules, powders, granules and oral solutionsor suspensions, sublingual, buccal, intratracheal, intraocular andintranasal administration forms, forms for administration by inhalation,topical, transdermal, subcutaneous, intramuscular or intravenousadministration forms, rectal administration forms, and implants. Fortopical application, the compounds according to the invention can beused in creams, gels, ointments or lotions.

By way of example, a unit administration form of a compound according tothe invention in tablet form can comprise the following constituents:

Compound according to the invention 50.0 mg Mannitol 223.75 mg  Sodiumcroscaramellose  6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose2.25 mg Magnesium stearate  3.0 mg

According to the usual practice, the dosage suitable for each patient isdetermined by the physician according to the mode of administration andthe weight and response of said patient.

The present invention relates to a compound of the formula (I), (I′) or(I″) according to the present invention, for use in treating cancer.

The present invention relates to a compound of formula (I), (I′) or (I″)as defined above, or an addition salt of this compound with apharmaceutically acceptable acid, for use as a medicine.

The present invention relates to a compound of formula (I), (I′) or (I″)as defined above, or a pharmaceutically acceptable salt of thiscompound, for use as a drug.

The present invention, according to another of its aspects, also relatesto a method for treating the pathological conditions indicated above,which comprises the administration, to a patient, of an effective doseof a compound according to the invention, or a pharmaceuticallyacceptable salt thereof.

Thus, the present invention also relates to a method for treating cancercomprising the administration, to a patient in need thereof, of apharmaceutically acceptable amount of a compound of formula (I), (I′) or(I″) as defined above, or a pharmaceutically acceptable salt thereof.

1-21. (canceled) 22: A process for preparing a compound of formula (I),or a pharmaceutically acceptable salt thereof:

wherein: R6 is —CONH₂ or a —C(R_(α))(R_(β))(OH) group in which R_(α) andR_(β) are both a hydrogen atom or R_(α) and R_(β) are identical and area (C₁-C₆) alkyl group; R is a phenyl or heteroaryl group substitutedwith R1, R′1, R2 and R3; R1 is a hydrogen atom or is selected from thegroup consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl andaryl, wherein the (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl or arylis optionally substituted with one or several substituents selected,independently in each instance, from the group consisting of amino,hydroxyl, thiol, halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio,(C₁-C₆)alkylamino, aryloxy, aryl(C₁-C₆)alkoxy, cyano, halo(C₁-C₆)alkyl,carboxyl and carboxy(C₁-C₆)alkyl; R′1 is a hydrogen atom or a(C₁-C₆)alkoxy group; R2 is selected from the group consisting of: ahydrogen atom, a halogen atom, a (C₁-C₆)alkyl group, a (C₃-C₇)cycloalkylgroup, a (C₁-C₆)alkoxy group; a heterocycloalkyl group, aheterocycloalkyl-CH₂— group, a heteroaryl group; wherein theheterocycloalkyl group, the heterocycloalkyl-CH₂— group or theheteroaryl group is optionally substituted with one or severalsubstituents selected, independently in each instance, from the groupconsisting of (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₆)alkoxy,heterocycloalkyl, carboxy(C₁-C₆)alkyl, NR4R5 and OR4; wherein the(C₁-C₆)alkyl group is optionally substituted with a halogen atom, a(C₁-C₆)alkoxy group, a heterocycloalkyl group, an NH₂ group or an OHgroup; and wherein R4 and R5 are each, independently of one another, ahydrogen atom, a (C₁-C₆)alkyl group or a heterocycloalkyl group; or elseR4 and R5 together form, with the nitrogen atom which bears them, a 4-to 7-membered ring; and an NRaRb group, wherein Ra and Rb are,independently of one another: a hydrogen atom; a heterocycloalkyl group,wherein the heterocycloalkyl group is optionally substituted with a(C₁-C₆)alkyl group; or a (C₁-C₆)alkyl group, wherein the (C₁-C₆)alkylgroup is optionally substituted with an NR4R5 group; wherein R4 and R5are each, independently of one another, a hydrogen atom, a (C₁-C₆)alkylgroup or a heterocycloalkyl group; or else R4 and R5 together form, withthe nitrogen atom which bears them, a 4- to 7-membered ring; R3 is ahydrogen atom, a halogen atom or a (C₁-C₆)alkyl group; wherein when R isa phenyl group, two adjacent substituents on the phenyl group maytogether form a heterocycloalkyl ring fused with the phenyl bearingthem, wherein the heterocycloalkyl ring is optionally substituted withone or several substituents selected, independently in each instance,from the group consisting of an oxo group and a (C₁-C₆)alkyl group; andR7 is an aryl group or a heteroaryl group, wherein the aryl group or theheteroaryl group is optionally substituted with one or severalsubstituents selected, independently in each instance, from the groupconsisting of cyano, halogen, (C₁-C₆)alkyl, OR′4, CH₂OH, CH₂NH₂,S(O)_(n)R′4, R8 and OR8; wherein: R′4 is a hydrogen atom, a (C₁-C₆)alkylgroup or an aryl group, wherein the (C₁-C₆)alkyl group or the aryl groupis optionally substituted with a halogen atom, an NH₂ group or an OHgroup; n is 1 or 2; and R8 is a halo(C₁-C₆)alkyl group; wherein each ofthe nitrogen atoms of the compound of formula (I), independently of oneanother, is optionally in N-oxide form, the process comprising: reactinga thienopyrimidine of formula (II):

wherein R7 is as defined above in formula (I); n is 1 or 2; and R16 is a(C₁-C₆)alkoxy group; with a compound of formula (IIIb):

wherein R is as defined above in formula (I), to produce a mixture; andi) when R6 is —CONH₂, treating the mixture with an aqueous ammoniasolution to obtain the compound of formula (I), or a pharmaceuticallyacceptable salt thereof, wherein R6 is —CONH₂; or ii) when R6 is a—C(R_(α))(R_(β))(OH) group and R_(α) and R_(β) are hydrogen atoms,reducing the mixture obtained with a reducing agent in a solvent toobtain the compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein R6 is a —C(R_(α))(R_(β))(OH) group and whereinR_(α) and R_(β) are hydrogen atoms; or iii) when R6 is a—C(R_(α))(R_(β))(OH) group and R_(α) and R_(β) are identical and are a(C₁-C₆)alkyl group, treating the mixture with an excess of anorganometallic derivative in a solvent to obtain the compound of formula(I), or a pharmaceutically acceptable salt thereof, wherein R6 is a—C(R_(α))(R_(β))(OH) group and wherein R_(α) and R_(β) are identical andare a (C₁-C₆)alkyl group. 23: The process of claim 22, wherein theorganometallic derivative is R_(α)MgX or R_(β)Li. 24: A process forpreparing a compound of formula (I), or a pharmaceutically acceptablesalt thereof:

wherein R6 is —CONH₂; R is a phenyl or heteroaryl group substituted withR1, R′1, R2 and R3; R1 is a hydrogen atom or is selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl and aryl,wherein the (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl or aryl isoptionally substituted with one or several substituents selected,independently in each instance, from the group consisting of amino,hydroxyl, thiol, halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio,(C₁-C₆)alkylamino, aryloxy, aryl(C₁-C₆)alkoxy, cyano, halo(C₁-C₆)alkyl,carboxyl and carboxy(C₁-C₆)alkyl; R′1 is a hydrogen atom or a(C₁-C₆)alkoxy group; R2 is selected from the group consisting of: ahydrogen atom, a halogen atom, a (C₁-C₆)alkyl group, a (C₃-C₇)cycloalkylgroup, a (C₁-C₆)alkoxy group; a heterocycloalkyl group, aheterocycloalkyl-CH₂— group, a heteroaryl group; wherein theheterocycloalkyl group, the heterocycloalkyl-CH₂— group or theheteroaryl group is optionally substituted with one or severalsubstituents selected, independently in each instance, from the groupconsisting of (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₆)alkoxy,heterocycloalkyl, carboxy(C₁-C₆)alkyl, NR4R5 and OR4; wherein the(C₁-C₆)alkyl group is optionally substituted with a halogen atom, a(C₁-C₆)alkoxy group, a heterocycloalkyl group, an NH₂ group or an OHgroup; and wherein R4 and R5 are each, independently of one another, ahydrogen atom, a (C₁-C₆)alkyl group or a heterocycloalkyl group; or elseR4 and R5 together form, with the nitrogen atom which bears them, a 4-to 7-membered ring; and an NRaRb group, wherein Ra and Rb are,independently of one another: a hydrogen atom; a heterocycloalkyl group,wherein the heterocycloalkyl group is optionally substituted with a(C₁-C₆)alkyl group; or a (C₁-C₆)alkyl group, wherein the (C₁-C₆)alkylgroup is optionally substituted with an NR4R5 group; wherein R4 and R5are each, independently of one another, a hydrogen atom, a (C₁-C₆)alkylgroup or a heterocycloalkyl group; or else R4 and R5 together form, withthe nitrogen atom which bears them, a 4- to 7-membered ring; R3 is ahydrogen atom, a halogen atom or a (C₁-C₆)alkyl group; wherein when R isa phenyl group, two adjacent substituents on the phenyl group maytogether form a heterocycloalkyl ring fused with the phenyl bearingthem, wherein the heterocycloalkyl ring is optionally substituted withone or several substituents selected, independently in each instance,from the group consisting of an oxo group and a (C₁-C₆)alkyl group; andR7 is an aryl group or a heteroaryl group, wherein the aryl group or theheteroaryl group is optionally substituted with one or severalsubstituents selected, independently in each instance, from the groupconsisting of cyano, halogen, (C₁-C₆)alkyl, OR′4, CH₂OH, CH₂NH₂,S(O)_(n)R′4, R8 and OR8; wherein: R′4 is a hydrogen atom, a (C₁-C₆)alkylgroup or an aryl group, wherein the (C₁-C₆)alkyl group or the aryl groupis optionally substituted with a halogen atom, an NH₂ group or an OHgroup; n is 1 or 2; and R8 is a halo(C₁-C₆)alkyl group; wherein each ofthe nitrogen atoms of the compound of formula (I), independently of oneanother, is optionally in N-oxide form, the process comprising: reactinga compound of formula (XII):

wherein R7 is as defined above in formula (I); and n is 1 or 2; with acompound of formula (IIIb)

wherein R is as defined above in formula (I); in the presence of anorganic or inorganic base in a polar aprotic solvent to obtain thecompound of formula (I), or a pharmaceutically acceptable salt thereof.25: A process for preparing a compound of formula (I), or apharmaceutically acceptable salt thereof:

wherein R6 is a —C(R_(α))(R_(β))(OH) group, wherein R_(α) and R_(β) are,independently of one another, a hydrogen atom or a (C₁-C₆)alkyl group,or together form, with the carbon atom which bears them, a 3- to5-membered carbocycle, R is a phenyl or heteroaryl group substitutedwith R1, R′1, R2 and R3; R1 is a hydrogen atom or is selected from thegroup consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl andaryl, wherein the (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl or arylis optionally substituted with one or several substituents selected,independently in each instance, from the group consisting of amino,hydroxyl, thiol, halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio,(C₁-C₆)alkylamino, aryloxy, aryl(C₁-C₆)alkoxy, cyano, halo(C₁-C₆)alkyl,carboxyl and carboxy(C₁-C₆)alkyl; R′1 is a hydrogen atom or a(C₁-C₆)alkoxy group; R2 is selected from the group consisting of: ahydrogen atom, a halogen atom, a (C₁-C₆)alkyl group, a (C₃-C₇)cycloalkylgroup, a (C₁-C₆)alkoxy group; a heterocycloalkyl group, aheterocycloalkyl-CH₂— group, a heteroaryl group; wherein theheterocycloalkyl group, the heterocycloalkyl-CH₂— group or theheteroaryl group is optionally substituted with one or severalsubstituents selected, independently in each instance, from the groupconsisting of (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₆)alkoxy,heterocycloalkyl, carboxy(C₁-C₆)alkyl, NR4R5 and OR4; wherein the(C₁-C₆)alkyl group is optionally substituted with a halogen atom, a(C₁-C₆)alkoxy group, a heterocycloalkyl group, an NH₂ group or an OHgroup; and wherein R4 and R5 are each, independently of one another, ahydrogen atom, a (C₁-C₆)alkyl group or a heterocycloalkyl group; or elseR4 and R5 together form, with the nitrogen atom which bears them, a 4-to 7-membered ring; and an NRaRb group, wherein Ra and Rb are,independently of one another: a hydrogen atom; a heterocycloalkyl group,wherein the heterocycloalkyl group is optionally substituted with a(C₁-C₆)alkyl group; or a (C₁-C₆)alkyl group, wherein the (C₁-C₆)alkylgroup is optionally substituted with an NR4R5 group; wherein R4 and R5are each, independently of one another, a hydrogen atom, a (C₁-C₆)alkylgroup or a heterocycloalkyl group; or else R4 and R5 together form, withthe nitrogen atom which bears them, a 4- to 7-membered ring; R3 is ahydrogen atom, a halogen atom or a (C₁-C₆)alkyl group; wherein when R isa phenyl group, two adjacent substituents on the phenyl group maytogether form a heterocycloalkyl ring fused with the phenyl bearingthem, wherein the heterocycloalkyl ring is optionally substituted withone or several substituents selected, independently in each instance,from the group consisting of an oxo group and a (C₁-C₆)alkyl group; andR7 is an aryl group or a heteroaryl group, wherein the aryl group or theheteroaryl group is optionally substituted with one or severalsubstituents selected, independently in each instance, from the groupconsisting of cyano, halogen, (C₁-C₆)alkyl, OR′4, CH₂OH, CH₂NH₂,S(O)_(n)R′4, R8 and OR8; wherein: R′4 is a hydrogen atom, a (C₁-C₆)alkylgroup or an aryl group, wherein the (C₁-C₆)alkyl group or the aryl groupis optionally substituted with a halogen atom, an NH₂ group or an OHgroup; n is 1 or 2; and R8 is a halo(C₁-C₆)alkyl group; wherein each ofthe nitrogen atoms of the compound of formula (I), independently of oneanother, is optionally in N-oxide form, the process comprising: reactinga compound of formula (XIV):

wherein R_(α) and R_(β) are as defined above in formula (I); R7 is asdefined above in formula (I); and n is 1 or 2; with a compound offormula (IIIb)

wherein R is as defined above in formula (I); in the presence of anorganic or inorganic base in a polar aprotic solvent to obtain thecompound of formula (I), or a pharmaceutically acceptable salt thereof.26: A compound of formula (II):

wherein: R7 is an aryl group or a heteroaryl group, wherein the arylgroup or the heteroaryl group is optionally substituted with one orseveral substituents selected, independently in each instance, from thegroup consisting of cyano, halogen, (C₁-C₆)alkyl, OR′4, CH₂OH, CH₂NH₂,S(O)_(n)R′4, R8 and OR8; wherein: R′4 is a hydrogen atom, a (C₁-C₆)alkylgroup or an aryl group, wherein the (C₁-C₆)alkyl group or the aryl groupis optionally substituted with a halogen atom, an NH₂ group or an OHgroup; n is 1 or 2; and R8 is a halo(C₁-C₆)alkyl group; and R16 is a(C₁-C₆)alkoxy group; or a pharmaceutically acceptable salt thereof. 27:A compound of formula (XII):

wherein: R7 is an aryl or a heteroaryl group, wherein the aryl group orthe heteroaryl group is optionally substituted with one or severalsubstituents selected, independently in each instance, from the groupconsisting of cyano, halogen, (C₁-C₆)alkyl, OR′4, CH₂OH, CH₂NH₂,S(O)_(n)R′4, R8 and OR8; wherein: R′4 is a hydrogen atom, a (C₁-C₆)alkylgroup or an aryl group, wherein the (C₁-C₆)alkyl group or the aryl groupis optionally substituted with a halogen atom, an NH₂ group or an OHgroup; n is 1 or 2; and R8 is a halo(C₁-C₆)alkyl group; or apharmaceutically acceptable salt thereof. 28: A compound of formula(XIV):

wherein: R_(α) and R_(β) are, independently of one another, a hydrogenatom or a (C₁-C₆)alkyl group or together form, with the carbon atomwhich bears them, a 3- to 5-membered carbocycle; R7 is an aryl or aheteroaryl group, wherein the aryl group or the heteroaryl group isoptionally substituted with one or several substituents selected,independently in each instance, from the group consisting of cyano,halogen, (C₁-C₆)alkyl, OR′4, CH₂OH, CH₂NH₂, S(O)_(n)R′4, R8 and OR8;wherein: R′4 is a hydrogen atom, a (C₁-C₆)alkyl group or an aryl group,wherein the (C₁-C₆)alkyl group or the aryl group is optionallysubstituted with a halogen atom, an NH₂ group or an OH group; n is 1 or2; and R8 is a halo(C₁-C₆)alkyl group; or a pharmaceutically acceptablesalt thereof.